Dosage forms comprising a CETP inhibitors and an HMG-CoA reductase inhibitor

ABSTRACT

A dosage form comprises (1) a solid amorphous dispersion comprising a cholesterol ester transfer protein inhibitor and an acidic concentration-enhancing polymer and (2) an HMG-CoA reductase inhibitor. The solid amorphous dispersion and the HMG-CoA reductase inhibitor are combined in the dosage form so that the solid amorphous dispersion and the HMG-CoA reductase inhibitor are substantially separate from one another in the dosage form.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority of provisional PatentApplication Ser. No. 60/435,345 filed Dec. 20, 2002, which isincorporated herein by reference in its entirety for all purposes.

BACKGROUND

The present invention relates to a dosage form comprising: (1) a solidamorphous dispersion comprising a cholesteryl ester transfer protein(CETP) inhibitor and an acidic concentration-enhancing polymer; and (2)an acid-sensitive HMG-CoA reductase inhibitor.

It is well known that inhibitors of 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMG-CoA reductase), an important enzyme catalyzing theintracellular synthesis of cholesterol, will bring about reduced levelsof blood cholesterol, especially in terms of the low density lipoproteinform of cholesterol. Therefore, HMG-CoA reductase enzyme inhibitors areconsidered potentially useful as hypocholesterolemic or hypolipidemicagents.

CETP inhibitors are another class of compounds that are capable ofmodulating levels of blood cholesterol such as, by raising high densitylipoprotein (HDL) cholesterol and lowering LDL cholesterol. CETPinhibitors have extremely low aqueous solubility. Accordingly, CETPinhibitors must be formulated so as to be capable of providing goodbioavailability. One method for increasing the bioavailability of a CETPinhibitor is to form a solid amorphous dispersion of the drug and aconcentration-enhancing polymer. See, e.g., WO02/11710 A2. For many CETPinhibitors, an acidic concentration-enhancing polymer provides thehighest level of enhancement.

It is well known that a combination therapy of a CETP inhibitor and anHMG-CoA reductase inhibitor may be used to treat elevated LDLcholesterol and low HDL cholesterol levels. For example, WO02/13797 A2relates to pharmaceutical combinations of cholesteryl ester transferprotein inhibitors and atorvastatin. The application discloses that thecompounds may be generally administered separately or together, with apharmaceutically acceptable carrier, vehicle or diluent. The compoundsmay be administered individually or together in any conventional oral,parenteral or transdermal dosage form. For oral administration, thecomposition may take the form of solutions, suspensions, tablets, pills,capsules, powders and the like.

DeNinno et al., U.S. Pat. No. 6,310,075 B1, relates to CETP inhibitors,pharmaceutical compositions containing such inhibitors and the use ofsuch inhibitors. DeNinno et al. disclose a pharmaceutical combinationcomposition comprising a CETP inhibitor and an HMG-CoA reductaseinhibitor. DeNinno disclose that the compounds of the invention may beadministered in the form of a pharmaceutical composition comprising atleast one of the compounds, together with a pharmaceutically acceptablevehicle, diluent, or carrier. For oral administration a pharmaceuticalcomposition can take the form of solutions, suspensions, tablets, pills,capsules, powders and the like. Similarly, DeNinno et al., U.S. Pat. No.6,197,786 B1, disclose pharmaceutical combinations comprising CETPinhibitors and HMG-CoA reductase inhibitors.

WO 00/38722 discloses combinations of CETP inhibitors and HMG-CoAreductase inhibitors for cardiovascular indications. The pharmaceuticalcompositions include those suitable for oral, rectal, topical, buccal,and parenteral administration. The application discloses solid dosageforms for oral administration including capsules, tablets, pills,powders, gel caps and granules.

Schmeck et al., U.S. Pat. No. 5,932,587, disclose another class of CETPinhibitors. Schmeck et al. disclose that the CETP inhibitors may be usedin combination with certain HMG-CoA reductase inhibitors such asstatins, including atorvastatin.

However, while it is desired to combine the CETP inhibitor and anHMG-CoA reductase inhibitor into a single dosage form, combining a CETPinhibitor and an HMG-CoA reductase inhibitor into a single dosage formpresents a number of potential problems. Some HMG-CoA reductaseinhibitor compounds are unstable in that they are susceptible to heat,moisture, low pH environment, and light. Some HMG-CoA reductaseinhibitors, such as atorvastatin, pravastatin, florastatin,rosuvastatin, and cerivastatin are in the form of hydroxy acids thatwill degrade to a lactone in an acidic environment. OtherHMG-CoA-reductase inhibitors, such as lovastatin and simvastatin,contain substituents that readily degrade in an acidic environment. Whenpackaged in the form of tablets, powders, granules, or within capsules,the HMG-CoA reductase inhibitor may be further destabilized by contactwith the molecular moieties of other components of the dosage form.Since pharmaceutical dosage form components such as binders, diluents,antiadherents, surfactants and the like may adversely interact with theactive ingredient compound, a stabilizing means may be required foreffective pharmaceutical dosages. For example, U.S. Pat. No. 6,126,971discloses the addition of a stabilizing agent such as calcium carbonateto stabilize the HMG-CoA reductase inhibitor atorvastatin calcium.Nevertheless, the means for stabilizing the HMG-CoA reductase inhibitormust also allow solubilization of the CETP inhibitor.

Accordingly, what is desired is a dosage form containing a CETPinhibitor and an HMG-CoA reductase inhibitor that stabilizes the HMG-CoAreductase inhibitor and that provides good bioavailability for the CETPinhibitor.

SUMMARY OF THE INVENTION

The present invention overcomes the drawbacks of the prior art byproviding a unitary dosage form comprising (1) a solid amorphousdispersion comprising a CETP inhibitor and an acidicconcentration-enhancing polymer and (2) an HMG-CoA reductase inhibitor.The solid amorphous dispersion and HMG-CoA reductase inhibitor arecombined in the dosage form so that the solid amorphous dispersion andthe HMG-CoA reductase inhibitor are substantially separate from oneanother in the dosage form.

By “unitary dosage form” is meant a single dosage form containing boththe CETP inhibitor and HMG-CoA reductase inhibitor so that, followingadministration of the unitary dosage form to a use environment, both theCETP inhibitor and HMG-CoA reductase inhibitor are delivered to the useenvironment. The term “unitary dosage form” includes a single tablet,caplet, pill, capsule, powder, and a kit comprising one or more tablets,caplets, pills, capsules, sachets, powders, or solutions intended to betaken together.

By “substantially separate from one another” is meant that a sufficientamount of the HMG-CoA reductase inhibitor is physically separated fromthe solid amorphous dispersion so that the acidicconcentration-enhancing polymer does not cause an unacceptable level ofchemical degradation of the HMG-CoA reductase inhibitor. The HMG-CoAreductase inhibitor thus has improved chemical stability relative to ablended mixture of (1) particles consisting essentially of the solidamorphous dispersion of the CETP inhibitor and acidicconcentration-enhancing polymer alone, and (2) particles consistingessentially of the HMG-CoA reductase inhibitor alone. This improvedchemical stability of the HMG-CoA reductase inhibitor is believed to berelated primarily to reducing the fraction of HMG-CoA reductaseinhibitor molecules that are in contact with the solid amorphousdispersion of CETP inhibitor/acidic concentration-enhancing polymer. Aswill be described below, there are many ways in which to formulate aunitary dosage form in which the solid amorphous dispersion and theHMG-CoA reductase inhibitor are substantially separate from one anther;that is, the unitary dosage form limits the fraction of HMG-CoAreductase inhibitor molecules that are in contact with the solidamorphous dispersion of the CETP inhibitor and acidicconcentration-enhancing polymer.

For some approaches, the separation is macroscopic in nature; that is,the HMG-CoA reductase inhibitor and the solid amorphous dispersion maybe, for example, in separate layers of the dosage form so that onlythose HMG-CoA reductase inhibitor molecules present at the interface ofthe two layers may be in contact with the solid amorphous dispersion.Further separation between the HMG-CoA reductase inhibitor and the solidamorphous dispersion may be obtained by providing a third layer thatseparates the two compositions. Alternatively, the unitary dosage formmay be in the form of a kit wherein the HMG-CoA reductase inhibitor andsolid amorphous dispersion are within separate compartments in thedosage form.

For other approaches, the separation is microscopic in nature; that is,the separation may be due to only one or more intervening molecules. Forexample, the unitary dosage form may comprise the solid amorphousdispersion and a plurality of relatively large particles or granulescomprising the HMG-CoA reductase inhibitor. The HMG-CoA reductaseinhibitor molecules located in the interior of the particles or granulesare separated from the solid amorphous dispersion by the molecules onthe surface of the particles or granules. Alternatively, the solidamorphous dispersion may be in the form of relatively large particles orgranules, with molecules of the acidic concentration-enhancing polymerin the solid amorphous dispersion on the interior of the particles orgranules being separated from the HMG-CoA reductase inhibitor by themolecules on the surface of the particles or granules. Alternatively,particles or granules of the HMG-CoA reductase inhibitor, particles orgranules of the solid amorphous dispersion, or both may be coated with aprotective coating, thus separating the HMG-CoA reductase inhibitor andthe solid amorphous dispersion. In any case, the HMG-CoA reductaseinhibitor and the solid amorphous dispersion are substantially separatedfrom one another so that the acidic concentration-enhancing polymer doesnot cause an unacceptable level of chemical degradation of the HMG-CoAreductase inhibitor.

Reference to a “use environment” can either mean in vivo fluids, such asthe GI tract, subdermal, intranasal, buccal, intrathecal, ocular,intraaural, subcutaneous spaces, vaginal tract, arterial and venousblood vessels, pulmonary tract or intramuscular tissue of an animal,such as a mammal and particularly a human, or the in vitro environmentof a test solution, such as phosphate buffered saline (PBS) or a ModelFasted Duodenal (MFD) solution. An appropriate PBS solution is anaqueous solution comprising 20 mM-sodium phosphate (Na₂HPO₄), 47 mMpotassium phosphate (KH₂PO₄), 87 mM NaCl, and 0.2 mM KCl, adjusted to pH6.5 with NaOH. An appropriate MFD solution is the same PBS solutionwherein additionally is present 7.3 mM sodium taurocholic acid and 1.4mM of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine.

“Administration” to a use environment means, where the in vivo useenvironment is the GI tract, delivery by ingestion or swallowing orother such means to deliver the drugs. One skilled in the art willunderstand that “administration” to other in vivo use environments meanscontacting the use environment with the composition of the inventionusing methods known in the art. See for example, Remington: The Scienceand Practice of Pharmacy, 20^(th) Edition (2000). Where the useenvironment is in vitro, “administration” refers to placement ordelivery of the dosage form to the in vitro test medium. Where releaseof drug into the stomach is not desired but release of the drug in theduodenum or small intestine is desired, the use environment may also bethe duodenum or small intestine. In such cases, “introduction” to a useenvironment is that point in time when the dosage form leaves thestomach and enters the duodenum.

The inventors have found that the bioavailability of CETP inhibitors maybe substantially improved by forming a solid amorphous dispersion of theCETP inhibitor and an acidic concentration-enhancing polymer. Theadministration of the CETP inhibitor in the form of a solid amorphousdispersion containing a concentration-enhancing polymer substantiallyincreases the concentration of dissolved CETP inhibitor in the useenvironment relative to administration of the CETP inhibitor incrystalline form. In particular, the use of certain acidicconcentration-enhancing polymers has yielded substantial improvements inbioavailability.

However, when an HMG-CoA reductase inhibitor is mixed directly with asolid amorphous dispersion of the CETP inhibitor and acidicconcentration-enhancing polymer and then granulated in a tabletingformulation, the inventors observe chemical degradation of the HMG-CoAreductase inhibitor that is greater than that observed for the HMG-CoAreductase inhibitor alone. The inventors solved the chemical degradationproblem by substantially physically separating the solid amorphousdispersion from the HMG-CoA reductase inhibitor while keeping thedispersion and the HMG-CoA reductase inhibitor in a unitary dosage form.The inventors believe that the chemical degradation was caused by theacidic concentration-enhancing polymer or indirectly by migration of theacid to the surface of the HMG-CoA reductase inhibitor. Surprisingly,the inventors found that the chemical stability of the HMG-CoA reductaseinhibitor in the unitary dosage form could be improved by granulatingthe CETP inhibitor solid amorphous dispersion separately from theHMG-CoA reductase inhibitor. Without wishing to be bound by a particulartheory, the inventors believe that when the granules comprising thesolid amorphous dispersion and granulation excipients are blended withthe HMG-CoA reductase inhibitor and then compressed into a tablet, thesolid amorphous dispersion is substantially separated from the HMG-CoAreductase inhibitor, thus stabilizing the HMG-CoA reductase inhibitor.Alternatively, other methods may be used to separate the solid amorphousdispersion from the HMG-CoA reductase inhibitor. In addition, the basicnature of the HMG-CoA reductase inhibitor itself, when, for example, itis a basic salt form, or the presence of one or more basic excipientsmay be used to shield the HMG-CoA reductase inhibitor from the acidicenvironment created by the solid amorphous dispersion.

The foregoing and other objectives, features, and advantages of theinvention will be more readily understood upon consideration of thefollowing detailed description of the invention, taken in conjunctionwith the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-8 are schematic drawings of cross sections of exemplaryembodiments of dosage forms of the present invention.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention combines a CETP inhibitor and an HMG-CoA reductaseinhibitor in a unitary dosage form. The CETP inhibitor is in the form ofa solid amorphous dispersion comprising an acidicconcentration-enhancing polymer. The solid amorphous dispersion iscombined with the HMG-CoA reductase inhibitor so that the solidamorphous dispersion and the HMG-CoA reductase inhibitor aresubstantially separate from one another in the dosage form. Unitarydosage forms, solid amorphous dispersions, drugs, excipients, andmethods for forming the dosage forms are discussed in more detail below.

Unitary Dosage Forms in which the CETP Inhibitor and HMG-CoA ReductaseInhibitor are Substantially Separate

The unitary dosage forms of the present invention comprise (1) a CETPinhibitor composition comprising a solid amorphous dispersion comprisinga CETP inhibitor and an acidic concentration-enhancing polymer, and (2)an HMG-CoA reductase inhibitor composition comprising the HMG-CoAreductase inhibitor. The two compositions are combined such that thesolid amorphous dispersion and the HMG-CoA reductase inhibitor aresubstantially separate from one another in the dosage form. The solidamorphous dispersion and the HMG-CoA reductase inhibitor should besubstantially physically separated, so that the acidicconcentration-enhancing polymer does not cause unacceptable levels ofchemical degradation of the HMG-CoA reductase inhibitor. The resultingunitary dosage form has improved chemical stability when compared to acontrol dosage form where the solid amorphous dispersion and the HMG-CoAreductase inhibitor are not substantially separate from one another.

The HMG-CoA reductase inhibitor and the acidic concentration-enhancingdispersion polymer are substantially physically separated in the dosageform. This means that the fraction of HMG-CoA reductase inhibitormolecules in contact with the acidic concentration-enhancing polymer inthe solid amorphous dispersion is sufficiently small so that the acidicenvironment generated by the acidic concentration-enhancing polymer doesnot lead to unacceptable levels of chemical degradation of the HMG-CoAreductase inhibitor. Separation of the HMG-CoA reductase inhibitor andthe acidic concentration-enhancing polymer results in improved chemicalstability of the HMG-CoA reductase inhibitor in the dosage form.

Several different methods may be used to separate the solid amorphousdispersion and HMG-CoA reductase inhibitor. In one method, the solidamorphous dispersion is granulated with optional granulation excipientsinto a CETP inhibitor granulation and then mixed with an HMG-CoAreductase inhibitor composition. When the acidic concentration-enhancingpolymer is present in a granule, the amount of acidicconcentration-enhancing polymer on the surface of the granule, which canpotentially be in contact with the HMG-CoA reductase inhibitorcomposition, is low due to the decrease in the surface to volume ratioresulting from the use of a large granule compared with a smaller solidamorphous dispersion particle. In addition, the optional granulationexcipients reduce the amount of acidic concentration-enhancing polymeron the outside surface of the granule. As a result, when the granulesare mixed with an HMG-CoA reductase inhibitor composition, the HMG-CoAreductase inhibitor and the acidic concentration-enhancing polymer aresubstantially separate, resulting in improved chemical stability of theHMG-CoA reductase inhibitor.

Thus, in one aspect, a unitary dosage form is provided in which thesolid amorphous dispersion of the CETP inhibitor and acidicconcentration-enhancing polymer is granulated and then mixed with theHMG-CoA reductase inhibitor, shown schematically as dosage form 10 inFIG. 1. Granules 12 comprising the solid amorphous dispersion of theCETP inhibitor and acidic concentration-enhancing polymer and optionalgranulation excipients are interspersed within the HMG-CoA reductaseinhibitor composition 14. The solid amorphous dispersion within thegranules are substantially separate from the HMG-CoA reductaseinhibitor. Dosage form 10 may optionally be coated with a conventionalcoating 16.

Alternatively, the HMG-CoA reductase inhibitor may be granulated withoptional granulation excipients and mixed with a CETP inhibitorcomposition. Thus, in another aspect, a unitary dosage form is providedin which the HMG-CoA reductase inhibitor is granulated and then mixedwith the solid amorphous dispersion of the CETP inhibitor and acidicconcentration-enhancing polymer, shown schematically as dosage form 20in FIG. 2. Granules 24 comprising the HMG-CoA reductase inhibitor andoptional granulation excipients are interspersed within the CETPinhibitor composition 22. The HMG-CoA reductase inhibitor particles inthe granules are substantially separate from the solid amorphousdispersion in the CETP inhibitor composition. Dosage form 20 mayoptionally be coated with a conventional coating 26.

In another method, the solid amorphous dispersion may be granulated withoptional granulation excipients into a CETP inhibitor granulation andthe HMG-CoA reductase inhibitor may be granulated with optionalgranulation excipients into an HMG-CoA reductase inhibitor granulationand the two granulations blended together. Thus, in another aspect, aunitary dosage form comprises a first granulation comprising the solidamorphous dispersion of the CETP inhibitor and the acidicconcentration-enhancing polymer mixed with a second granulationcomprising the HMG-CoA reductase inhibitor, shown schematically asdosage form 30 in FIG. 3. Here, the CETP inhibitor granulation 32 ismixed with the HMG-CoA reductase inhibitor granulation 34. Surprisingly,the inventors have found that the stability of the HMG-CoA reductaseinhibitor may be maintained by mixing the two granulations together. Incontrast, granulating the solid amorphous dispersion, HMG-CoA reductaseinhibitor, and other excipients all together yields a composition inwhich the HMG-CoA reductase inhibitor chemically degrades. Dosage form30 may optionally be coated with a conventional coating 36.

As yet another method, the CETP inhibitor composition comprises a solidamorphous dispersion coated with a material that is not acidic. Thiscomposition is mixed with an HMG-CoA reductase inhibitor composition, soas to prevent contact of the solid amorphous dispersion with the HMG-CoAreductase inhibitor. Alternatively, the HMG-CoA reductase inhibitorcomposition may be coated with a material that is not acidic and thenmixed with the CETP inhibitor composition, so as to prevent contact ofthe solid amorphous dispersion with the HMG-CoA reductase inhibitor. Ineither case, the coating is sufficiently thick to ensure the HMG-CoAreductase inhibitor and the solid amorphous dispersion are substantiallyseparate, resulting in improved chemical stability.

Thus, in one aspect, a unitary dosage form is provided in which the CETPinhibitor composition comprises a solid amorphous dispersion coated witha coating and blended with the HMG-CoA reductase inhibitor, shownschematically as dosage form 40 in FIG. 4. The solid amorphousdispersion 42 is coated with a coating 45. In one embodiment, the solidamorphous dispersion is coated with a protective coating that is notacidic. The coating substantially separates the solid amorphousdispersion from the HMG-CoA reductase inhibitor. The coating may be anyconventional coating that does not contain acidic groups, or othermaterial that would adversely interact with either the solid amorphousdispersion or the HMG-CoA reductase inhibitor. The coated solidamorphous dispersion is then mixed with the HMG-CoA reductase inhibitorcomposition 44. Dosage form 40 may optionally be coated with aconventional coating 46.

In another aspect, a unitary dosage form is provided in which theHMG-CoA reductase inhibitor composition comprises an HMG-CoA reductaseinhibitor coated with a non-acidic coating. The HMG-CoA reductaseinhibitor composition is then blended with the solid amorphousdispersion, shown schematically as dosage form 50 in FIG. 5. The HMG-CoAreductase inhibitor 54 is coated with a coating 55. The coatingsubstantially separates the solid amorphous dispersion from the HMG-CoAreductase inhibitor. The coating may be any conventional coating thatdoes not contain acidic groups, or other material that would adverselyinteract with either the solid amorphous dispersion or the HMG-CoAreductase inhibitor. The coated HMG-CoA reductase inhibitor is thenmixed with the solid amorphous dispersion 52. Dosage form 50 mayoptionally be coated with a conventional coating 56.

As yet another method, the CETP inhibitor composition and the HMG-CoAreductase inhibitor composition may be formed into separate regions orvolumes of the dosage form, such as separate layers. Thus, in oneaspect, a unitary dosage form is provided in which the CETP inhibitorcomposition and the HMG-CoA reductase inhibitor composition are inseparate layers or volumes within the dosage form. In one embodiment,the dosage form is a bi-layer tablet, shown schematically as dosage form60 in FIG. 6. The dosage form 60 has a first layer 62 consisting of theCETP inhibitor composition, and a second layer 64 consisting of theHMG-CoA reductase inhibitor composition. The dosage form 60 mayoptionally be coated with a conventional coating 66. The layers 62 and64 may be formed by any conventional method, as described below. Byseparating the CETP inhibitor composition and the HMG-CoA reductaseinhibitor composition into two separate layers, the solid amorphousdispersion and HMG-CoA reductase inhibitor are substantially separatefrom one another. This results in acceptably low rates of degradation ofthe HMG-CoA reductase inhibitor.

Another embodiment of a unitary dosage form is a trilayer dosage formhaving three layers. FIG. 7 shows schematically a trilayer dosage form70 having layers 72, 74 and 78. One or more of layers 72, 74 and 78 maybe the CETP inhibitor composition, and one or more of layers 72, 74, and78 may be the HMG-CoA reductase inhibitor composition. Trilayer dosageforms may be formed by any conventional method, as described below.Again, by separating the CETP inhibitor composition and the HMG-CoAreductase inhibitor composition into separate layers, the solidamorphous dispersion and HMG-CoA reductase inhibitor are substantiallyseparate from one another, resulting in acceptably low rates ofdegradation of the HMG-CoA reductase inhibitor. Dosage form 70 mayoptionally be coated with a conventional coating 76.

In a specific embodiment of the trilayer dosage form 70, layer 78comprises a non-acidic barrier layer, separating the CETP inhibitorcomposition 72 from the HMG-CoA reductase inhibitor composition 74. Thebarrier layer ensures the solid amorphous dispersion and HMG-CoAreductase inhibitor are substantially separate from one another,resulting in acceptably low rates of degradation of the HMG-CoAreductase inhibitor.

In another embodiment (not shown), the unitary dosage form has more thanthree layers. At least one layer is the CETP inhibitor composition, andat least one layer is the HMG-CoA reductase inhibitor composition.Optionally, at least one of the layers is a non-acidic barrier layer.The layers are arranged so that the solid amorphous dispersion andHMG-CoA reductase inhibitor are substantially separate from one another.

Yet another embodiment of a unitary dosage form is a concentric coredosage form having a central core and an outer layer surrounding thecore. FIG. 8 shows schematically a dosage form 80 having a central core82 and a layer 84 surrounding the core 82. The CETP inhibitorcomposition may be in the central core 82 with the HMG-CoA reductaseinhibitor composition in the surrounding layer 84, or the HMG-CoAreductase inhibitor composition may be in the central core 82 with theCETP inhibitor composition in the surrounding layer 84. By separatingthe CETP inhibitor composition and the HMG-CoA reductase inhibitorcomposition into separate volumes, the solid amorphous dispersion andHMG-CoA reductase inhibitor are substantially separate from one another,resulting in acceptably low rates of degradation of the HMG-CoAreductase inhibitor. The central core may optionally be coated with anon-acidic protective coating to ensure the solid amorphous dispersionand HMG-CoA reductase inhibitor are substantially separate from oneanother. Dosage form 80 may optionally be coated with a conventionalcoating 86.

The unitary dosage form may be in the form of a tablet, caplet, pill,capsule, powder or other dosage form known in the art. In oneembodiment, the CETP inhibitor composition and HMG-CoA reductaseinhibitor composition are blended together and then compressed to form atablet, caplet, pill, or other dosage forms formed by compression forcesknown in the art. Examples of suitable tablets are shown in FIGS. 1-8.

Yet another embodiment of the unitary dosage form is a capsule. The CETPinhibitor composition and the HMG-CoA reductase inhibitor compositionare mixed and placed into a suitable capsule, such as a hard gelatincapsule or a soft gelatin capsule, well known in the art (see, forexample, Remington's Pharmaceutical Sciences, (18th ed. 1990)). Thecompositions are formed such that the solid amorphous dispersion and theHMG-CoA reductase inhibitor are substantially separate in the dosageform. In one embodiment, the CETP inhibitor composition is firstgranulated and then mixed with the HMG-CoA reductase inhibitorcomposition and the mixture placed into a capsule. In anotherembodiment, the HMG-CoA reductase inhibitor composition is firstgranulated and then mixed with the CETP inhibitor composition and themixture placed into a capsule. In yet another embodiment, the CETPinhibitor composition is granulated and mixed with a granulation of theHMG-CoA reductase inhibitor composition. In still another embodiment,the CETP inhibitor composition comprises a solid amorphous dispersionthat has been coated with a protective coating. The coated solidamorphous dispersion is then mixed with the HMG-CoA reductase inhibitorcomposition and the mixture placed into a capsule. In yet anotherembodiment, the HMG-CoA reductase inhibitor composition comprises coatedHMG-CoA reductase inhibitor particles. The coated particles are mixedwith the CETP inhibitor composition and the mixture placed into acapsule. In yet another embodiment, the HMG-CoA reductase inhibitorcomposition comprises a compressed tablet comprising the HMG-CoAreductase inhibitor and optional excipients. The HMG-CoA reductaseinhibitor tablet is placed into a capsule with a CETP inhibitorcomposition. In yet another embodiment, the CETP inhibitor compositioncomprises a compressed tablet comprising the solid amorphous dispersionand optional excipients. The CETP inhibitor tablet is placed into acapsule with an HMG-CoA reductase inhibitor composition.

Yet another embodiment of the unitary dosage form is a powder, oftenreferred to in the art as a sachet or oral powder for constitution(OPC). The CETP inhibitor composition and the HMG-CoA reductaseinhibitor composition are mixed and placed into a suitable container,such as a pouch, bottle, box, bag, or other container known in the art.The compositions are formed such that the solid amorphous dispersion andthe HMG-CoA reductase inhibitor are substantially separate in the dosageform, as described above. The powder dosage form can then be taken dryor mixed with a liquid to form a paste, suspension or slurry prior todosing.

Yet another embodiment of the unitary dosage form is a kit comprisingtwo separate compositions: (1) one containing the solid amorphousdispersion comprising a CETP inhibitor and an acidicconcentration-enhancing polymer, and (2) one containing the HMG-CoAreductase inhibitor. The kit is designed such that the HMG-CoA reductaseinhibitor and the solid amorphous dispersion are substantially separate.The kit includes means for containing the separate compositions such asa divided bottle or a divided foil packet; however, the separatecompositions may also be contained within a single, undivided container.Typically the kit includes directions for the administration of theseparate components.

Chemical Stability

Dosage forms in which the solid amorphous dispersion and HMG-CoAreductase inhibitor are substantially separate from one another exhibitacceptably low rates of degradation of the HMG-CoA reductase inhibitorin the dosage form. The compositions and dosage forms of the presentinvention provide improved chemical stability of the HMG-CoA reductaseinhibitor relative to a control composition consisting of an equivalentquantity of the solid amorphous dispersion and HMG-CoA reductaseinhibitor wherein the solid amorphous dispersion and the HMG-CoAreductase inhibitor is not substantially separate, as described indetail below.

In general, degradation of the HMG-CoA reductase inhibitor may bemeasured using any conventional method for measuring the potency orpurity of drug in a pharmaceutical composition. For example, the amountof active HMG-CoA reductase inhibitor present in a composition may beinitially measured using high-performance liquid chromatography (HPLC)or other analytical techniques well known in the art. Alternatively, theamount of HMG-CoA reductase inhibitor initially present may becalculated from the amount of drug present in the composition. Thepotency of the composition is then measured after storage at controlledtemperature and humidity conditions for an appropriate period of time. Adecrease in potency indicates that a chemical reaction has occurred,leading to a decrease in the amount of active drug present in the cormposition, and is an indication of poor chemical stability.

An alternative method used to evaluate chemical stability is to analyzethe rate of increase in the amount of drug degradant(s) in thecomposition, which would indicate reaction of the HMG-CoA reductaseinhibitor. An HPLC or other analytical technique may be used todetermine the concentration of drug degradant(s) in a composition. Theamount of the degradant(s) is measured before and after storage undercontrolled storage conditions. The amount of increase in the drugdegradant(s) may be used to determine the amount of decrease in “percentdrug purity,” defined as 100 times the total amount of drug presentdivided by the amount of drug initially present. Thus, percent drugpurity may be calculated as follows:

${{{percent}\mspace{14mu}{drug}\mspace{14mu}{purity}} = {100 \times \left( \frac{{total}\mspace{14mu}{drug}\mspace{14mu}{present}}{{drug}\mspace{14mu}{initially}\mspace{14mu}{present}} \right)}}{\mspace{11mu}\mspace{14mu}}$

When the drug purity is calculated from the total amount of impurities,percent drug purity may be calculated by assuming that the druginitially present, given in wt %, is equal to 100 wt % minus the wt % oftotal initial impurities, and that total drug present is equal to 100 wt% minus the wt % of total impurities after storage, that is, at somelater time. This method of calculating percent drug purity is by theformula:

${{percent}\mspace{14mu}{drug}\mspace{14mu}{purity}} = {100 \times \left\lbrack {1 - \left( \frac{{total}\mspace{14mu}{impurities}}{{drug}\mspace{14mu}{initially}\mspace{14mu}{present}} \right)} \right\rbrack}$

The rate at which drug degradation occurs is generally dependent on thestorage conditions. The HMG-CoA reductase inhibitor, when formulated ina composition of the present invention, should be stable at ambienttemperature and humidity conditions (e.g., 20% to 60% relative humidity(RH)) for long periods of time, such as months or years. However, toexpedite testing, the storage conditions may employ elevated temperatureand/or humidity to simulate longer storage times at ambient conditions.The storage time may vary from a few days to weeks or months, dependingon the reactivity of the drug and the storage conditions.

A “degree of degradation” of drug following storage may be determined bysubtracting the final percent drug purity (determined either bymeasuring the decrease in drug present or the increase in drugimpurities present) from the initial percent drug purity. For example, asample of composition initially containing 100 mg HMG-CoA reductaseinhibitor and having no measurable impurities would have an initialpercent drug purity of 100 wt %. If, after storage, the amount ofHMG-CoA reductase inhibitor in the sample decreases to 95 mg, the finalpercent drug purity would be 95 wt % and the degree of degradation wouldbe 100 wt % less 95 wt %, or 5 wt %. Alternatively, if 100 mg of HMG-CoAreductase inhibitor were found to initially have 1 mg of impuritiespresent, it would have an initial percent drug purity of 99 wt %. If,after storage, the total impurities present had increased to 6 wt %, thefinal percent drug purity would be 94 wt % and the degree of degradationwould be 99 wt % less 94 wt %, or 5 wt %.

Alternatively, degree of degradation can be determined by subtractingthe amount of one or more specific drug degradants initially presentfrom the amount of that specific degradant present after storage. Such ameasure is useful where there are several drug degradants, of which onlyone or a few is of concern. For example, if an HMG-CoA reductaseinhibitor initially contained a specific degradant at a concentration of1 wt % and after storage the concentration of that degradant was 6 wt %,the degree of degradation would be 6 wt % less 1 wt %, or 5 wt %.

A relative degree of improvement in chemical stability of the HMG-CoAreductase inhibitor in a test composition may be determined by takingthe ratio of the degree of degradation of the HMG-CoA reductaseinhibitor in a control composition and the degree of degradation of theHMG-CoA reductase inhibitor in a test composition under the same storageconditions for the same storage time period. The test composition issimply the composition of the solid amorphous dispersion of the CETPinhibitor and acidic concentration-enhancing polymer, the HMG-CoAreductase inhibitor, and optional additional excipients, in which theunitary dosage form is prepared so that the solid amorphous dispersionand the HMG-CoA reductase inhibitor are substantially separate from oneanother. The control composition is simply the same amount of the solidamorphous dispersion of the CETP inhibitor and acidicconcentration-enhancing polymer, the HMG-CoA reductase inhibitor, andoptional additional excipients, in which the solid amorphous dispersion,HMG-CoA reductase inhibitor and optional additional excipients areblended together in a single step and then compressed to form a slug.The slug may-be milled to a smaller granule to ease testing of thecontrol composition. For example, where the degree of degradation of theHMG-CoA reductase inhibitor in a test composition is 1 wt %, and thedegree of degradation of the HMG-CoA reductase inhibitor in a controlcomposition is 5 wt %, the relative degree of improvement is 5 wt %/1 wt% equals 5.0. For compositions and dosage forms in which the HMG-CoAreductase inhibitor and solid amorphous dispersion are substantiallyseparate from one another, the relative degree of improvement is atleast 1.1. Preferably, the relative degree of improvement is at least1.25, more preferably at least 2.0, and even more preferably at least3.0, more preferably at least 5.0. In fact, some compositions of thepresent invention may achieve a relative degree of improvement greaterthan 20.

The particular storage conditions and time of storage may be chosen asconvenient depending on the degree of acid-sensitivity of the HMG-CoAreductase inhibitor, the particular acidic concentration-enhancingpolymer used in the solid amorphous dispersion, and the ratio of HMG-CoAreductase inhibitor to polymer in the composition. Where the HMG-CoAreductase inhibitor is particularly acid-sensitive, or where thecomposition has a low ratio of HMG-CoA reductase inhibitor to polymer,then shorter storage time periods may be used. Where the rate ofdegradation is linear, the relative degree of improvement will beindependent of the storage time. However, where the rate of degradationis non-linear under controlled storage conditions, the stability testused to compare the test composition with the control composition ispreferably chosen such that the degree of degradation is sufficientlylarge that it may be accurately measured. Typically, the time period ischosen so as to observe a degree of degradation in the controlcomposition of at least 0.1 wt % to 0.2 wt %. However, the time periodis not so long that the ratio of HMG-CoA reductase inhibitor to polymerchanges substantially. Typically, the time period is such that theobserved degree of degradation for the test composition is less than 50wt % and preferably less than 20 wt %. When rate of degradation in thecontrol composition is relatively slow, the test is preferably conductedover a long enough period of time under controlled storage conditions toallow a meaningful comparison of the stability of the test compositionwith the control composition.

A stability test which may be used to test whether a composition ordosage form meets the chemical stability criteria described above isstorage of the test dispersion and the control dispersion for six monthsat 40° C. and 75% relative humidity (RH) or for 3 months at 50□C and 75%RH. A relative degree of improvement may become apparent within ashorter time, such as three to five days, and shorter storage times maybe used for some very acid-sensitive HMG-CoA reductase inhibitors. Whencomparing dispersions under storage conditions that approximate ambientconditions, e.g., 30° C. and 60% RH, the storage period may need to beseveral months or up to two years.

In addition, it is preferred that the compositions comprising an HMG-CoAreductase inhibitor and a solid amorphous dispersion result in chemicalstability such that the HMG-CoA reductase inhibitor has a degree ofdegradation of less than about 5 wt %, more preferably less than about 2wt %, even more preferably less than about 0.5 wt %, and most preferablyless than about 0.1 wt % when stored at 40° C. and 75% RH for sixmonths, or less than about 5 wt %, more preferably less than about 2 wt%, even more preferably less than about 0.5 wt %, and more preferablyless than about 0.1 wt %, when stored at 30° C. and 60% RH for one year.Nevertheless, the compositions of the present invention may have adegree of degradation that is much greater than the preferred values, solong as the solid amorphous dispersion achieves the degree ofimprovement relative to a control composition as described above.

Cholesteryl Ester Transfer Protein Inhibitors

The CETP inhibitor may be any compound capable of inhibiting thecholesteryl ester transfer protein. Solid amorphous dispersions areparticularly useful for CETP inhibitors that have sufficiently lowaqueous solubility, low bioavailability or slow rate of absorption suchthat it is desirable to increase their concentration in an aqueousenvironment of use. The CETP inhibitor is typically “sparinglywater-soluble,”which means that the CETP inhibitor has a minimum aqueoussolubility of less than about 1 to 2 mg/mL at any physiologicallyrelevant pH (e.g., pH 1-8) and at about 22° C. Many CETP inhibitors are“substantially water-insoluble,” which means that the CETP inhibitor hasa minimum aqueous solubility of less than about 0.01 mg/mL (or 10 μg/ml)at any physiologically relevant pH (e.g., pH 1-8) and at about 22° C.(Unless otherwise specified, reference to aqueous solubility herein andin the claims is determined at about 22° C.) Compositions of the presentinvention find greater utility as the solubility of the CETP inhibitorsdecreases, and thus are preferred for CETP inhibitors with solubilitiesless than about 10 μg/mL, and even more preferred for CETP inhibitorswith solubilities less than about 1 μg/mL. Many CETP inhibitors haveeven lower solubilities (some even less than 0.1 μg/mL), and requiredramatic concentration enhancement to be sufficiently bioavailable uponoral dosing for effective plasma concentrations to be reached atpractical doses.

In general, the CETP inhibitor has a dose-to-aqueous solubility ratiogreater than about 100 mL, where the solubility (mg/mL) is the minimumvalue observed in any physiologically relevant aqueous solution (e.g.,those with pH values from 1 to 8) including USP simulated gastric andintestinal buffers, and dose is in mg. Compositions of the presentinvention, as mentioned above, find greater utility as the solubility ofthe CETP inhibitor decreases and the dose increases. Thus, thecompositions are preferred as the dose-to-solubility ratio increases,and thus are preferred for dose-to-solubility ratios greater than 1000mL, and more preferred for dose-to-solubility ratios greater than about5000 ml. The dose-to-solubility ratio may be determined by dividing thedose (in mg) by the aqueous solubility (in mg/ml).

Oral delivery of many CETP inhibitors is particularly difficult becausetheir aqueous solubility is usually extremely low, typically being lessthan 2 μg/ml, often being less than 0.1 μg/ml. Such low-solubilities area direct consequence of the particular structural characteristics ofspecies that bind to CETP and thus act as CETP inhibitors. This lowsolubility is primarily due to the hydrophobic nature of CETPinhibitors. Log P, defined as the base 10 logarithm of the ratio of thedrug solubility in octanol to the drug solubility in water, is a widelyaccepted measure of hydrophobicity. Log P may be measured experimentallyor calculated using methods known in the art. Calculated Log P valuesare often referred to by the calculation method, such as Alog P, Clog P,and Mlog P. In general, Log P values for CETP inhibitors are greaterthan 4 and are often greater than 5. Thus, the hydrophobic and insolublenature of CETP inhibitors as a class pose a particular challenge fororal delivery. Achieving therapeutic drug levels in the blood by oraldosing of practical quantities of drug generally requires a largeenhancement in drug concentrations in the gastrointestinal fluid and aresulting large enhancement in bioavailability. Such enhancements indrug concentration in gastrointestinal fluid typically need to be atleast about 10-fold and often at least about 50-fold or even at leastabout 200-fold to achieve desired blood levels. Surprisingly, the solidamorphous dispersions of the present invention have proven to have therequired large enhancements in drug concentration and bioavailability.

In contrast to conventional wisdom, the relative degree of enhancementin aqueous concentration and bioavailability provided by the solidamorphous dispersions generally improves for CETP inhibitors assolubility decreases and hydrophobicity increases. In fact, theinventors have recognized a subclass of these CETP inhibitors that areessentially aqueous insoluble, highly hydrophobic, and are characterizedby a set of physical properties. This subclass exhibits dramaticenhancements in aqueous concentration and bioavailability whenformulated using a solid amorphous dispersion.

The first property of this subclass of essentially insoluble,hydrophobic CETP inhibitors is extremely low aqueous solubility. Byextremely low aqueous solubility is meant that the minimum aqueoussolubility at physiologically relevant pH (pH of 1 to 8) is less thanabout 10 μg/ml and preferably less than about 1 μg/ml.

A second property is a very high dose-to-solubility ratio. Extremely lowsolubility often leads to poor or slow absorption of the drug from thefluid of the gastrointestinal tract, when the drug is dosed orally in aconventional manner. For extremely low solubility drugs, poor absorptiongenerally becomes progressively more difficult as the dose (mass of druggiven orally) increases. Thus, a second property of this subclass ofessentially insoluble, hydrophobic CETP inhibitors is a very high dose(in mg) to solubility (in mg/ml) ratio (ml). By “very highdose-to-solubility ratio” is meant that the dose-to-solubility ratio hasa value of at least 1000 ml, and preferably at least 5,000 ml, and morepreferably at least 10,000 ml.

A third property of this subclass of essentially insoluble, hydrophobicCETP inhibitors is that they are extremely hydrophobic. By extremelyhydrophobic is meant that the Log P value of the drug, has a value of atleast 4.0, preferably a value of at least 5.0, and more preferably avalue of at least 5.5.

A fourth property of this subclass of essentially insoluble CETPinhibitors is that they have a low melting point. Generally, drugs ofthis subclass will have a melting point of about 150° C. or less, andpreferably about 140° C. or less.

Primarily, as a consequence of some or all of these four properties,CETP inhibitors of this subclass typically have very low absolutebioavailabilities. Specifically, the absolute bioavailability of drugsin this subclass when dosed orally in their undispersed state is lessthan about 10% and more often less than about 5%.

For this subclass of CETP inhibitors, the CETP inhibitor, when dispersedin the solid amorphous dispersion, should be at least substantiallyamorphous, and more preferably is almost completely amorphous, asdescribed below. In addition, the solid amorphous dispersion should besubstantially homogeneous. As discussed below, such dispersions may bemade by mechanical processes, such as milling and extrusion; meltprocesses, such as fusion, melt-extrusion, and melt-congealing; andsolvent processes, such as non-solvent precipitation, spray coating, andspray-drying. When prepared in this fashion, this class of essentiallyinsoluble, hydrophobic CETP inhibitors often exhibits dramaticenhancements in aqueous concentration in the use environment and inbioavailability when dosed orally. While the degree of enhancement willdepend on the particular concentration-enhancing polymer, when preferredconcentration-enhancing polymers are used (as discussed below), suchcompositions may provide a maximum drug concentration (MDC) in anaqueous use environment that is at least about 50-fold, and preferablyat least about 200-fold, the equilibrium concentration of a controlcomposition comprising an equivalent quantity of the essentiallyinsoluble, hydrophobic CETP inhibitor but free from theconcentration-enhancing polymer. Likewise, the compositions also displayin an aqueous use environment an area under the concentration versustime curve (AUC), for any period of at least 90 minutes between the timeof introduction into the use environment and about 270 minutes followingintroduction into the use environment that is at least about 25-fold,and preferably at least about 100-fold, that of the control compositioncomprising an equivalent quantity of drug but free from theconcentration-enhancing polymer.

In the following, by “pharmaceutically acceptable forms” thereof ismeant any pharmaceutically acceptable derivative or variation, includingstereoisomers, stereoisomer mixtures, enantiomers, solvates, hydrates,isomorphs, polymorphs, salt forms and prodrugs.

One class of CETP inhibitors that finds utility with the presentinvention consists of oxy substituted4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines having the FormulaI

and pharmaceutically acceptable forms thereof;

wherein R_(I-1) is hydrogen, Y_(I), W_(I)—X_(I), W_(I)—Y_(I);

wherein W_(I) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_(I) is —O—Y_(I), —S—Y_(I), —N(H)—Y, or —N—(Y_(I))₂;

wherein Y_(I) for each occurrence is independently Z_(I) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(I);

wherein Z_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(I) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxyl, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

R_(I-3) is hydrogen or Q_(I);

wherein Q_(I) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(I);

wherein V_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(I) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carbamoyl, mono-N— or di-N,N—(C₁-C₆) alkylcarbamoyl, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

R_(I-4) is Q_(I-1) or V_(I-1)

wherein Q_(I-1) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(I-1);

wherein V_(I-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(I-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N— ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

wherein either R_(I-3) must contain V_(I) or R_(I-4) must containV_(I-1); and R_(I-5), R_(I-6), R_(I-7) and R_(I-8) are eachindependently hydrogen, hydroxy or oxy wherein said oxy is substitutedwith T_(I) or a partially saturated, fully saturated or fullyunsaturated one to twelve membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen and said carbon is optionally mono-, di- ortri-substituted independently with halo, said carbon is optionallymono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with T_(I);

wherein T_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(I) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines.

Compounds of Formula I are disclosed in commonly assigned U.S. Pat. No.6,140,342, the complete disclosure of which is herein incorporated byreference.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula I:

-   [2R,4S]4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-dinitro-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(2,6-dichloro-pyridin-4-ylmethyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester,-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-ethoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid 2,2,2-trifluoro-ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid propyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid tert-butyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester,-   [2R,4S]    (3,5-bis-trifluoromethyl-benzyl)-(1-butyryl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic    acid methyl ester;-   [2R,4S]    (3,5-bis-trifluoromethyl-benzyl)-(1-butyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic    acid methyl ester;-   [2R,4S]    (3,5-bis-trifluoromethyl-benzyl)-[1-(2-ethyl-butyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-carbamic    acid methyl ester, hydrochloride

Another class of CETP inhibitors that finds utility with the presentinvention consists of4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines, having theFormula II

and pharmaceutically acceptable forms thereof;

wherein R_(II-1), is hydrogen, Y_(II), W_(II)—X_(II), W_(II)—Y_(II);

wherein W_(II) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_(II) is —O—Y_(II), —S—Y_(II), —N(H)—Y_(II), or —N—(Y_(II))₂;

wherein Y_(II) for each occurrence is independently Z_(II) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(II);

Z_(II) is a partially saturated, fully saturated or fully unsaturatedthree to twelve membered ring optionally having one to four heteroatomsselected independently from oxygen, sulfur and nitrogen, or a bicyclicring consisting of two fused partially saturated, fully saturated orfully unsaturated three to six membered rings, taken independently,optionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen;

wherein said Z_(II) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl is also optionally substituted with from one to ninefluorines;

R_(II-3) is hydrogen or Q_(II);

wherein Q_(II) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(II);

wherein V_(II) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(II) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N— or di-N,N—(C₁-C₆) alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino or said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are optionally substitutedwith from one to nine fluorines;

R_(II-) ₄ is Q_(II-1) or V_(II-1)

wherein Q_(II-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(II-1);

wherein V_(II-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(II-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N— ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁₋₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isoptionally substituted with from one to nine fluorines;

wherein either R_(II-3) must contain V_(II) or R_(II-4) must containV_(II); and

R_(II-5), R_(II-6), R_(II-7) and R_(II-8) are each independentlyhydrogen, a bond, nitro or halo wherein said bond is substituted withT_(II) or a partially saturated, fully saturated or fully unsaturated(C₁-C₁₂) straight or branched carbon chain wherein carbon may optionallybe replaced with one or two heteroatoms selected independently fromoxygen, sulfur and nitrogen wherein said carbon atoms are optionallymono-, di- or tri-substituted independently with halo, said carbon isoptionally mono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T_(II);

wherein T_(II) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(II) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; provided that at least one of substituents R_(II-5),R_(II-6), R_(II-7) and R_(II-8) is not hydrogen and is not linked to thequinoline moiety through oxy.

Compounds of Formula II are disclosed in commonly assigned U.S. Pat. No.6,147,090, the complete disclosure of which is herein incorporated byreference.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula II:

-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2,6,7-trimethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester    [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-diethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-ethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester.-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of annulated4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines, having theFormula IIII

and pharmaceutically acceptable forms thereof;

wherein R_(III-1) is hydrogen, Y_(III), W_(III)—X_(III),W_(III)—Y_(III);

wherein W_(III) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_(III) is —O—Y_(III), —S—Y_(III), —N(H)—Y_(III) or —N—(Y_(III))₂;

Y_(III) for each occurrence is independently Z_(III) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(III);

wherein Z_(III) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(III) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl optionally substituted with from one to nine fluorines;

R_(III-3) is hydrogen or Q_(III);

wherein Q_(III) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(III);

wherein V_(III) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(III) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N— or di-N,N—(C₁-C₆) alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino or said(C₁-C₆)alkyl or (C₂-C₆)alkenyl are optionally substituted with from oneto nine fluorines;

R_(III-4) is Q_(III-1) or V_(III-1);

wherein Q_(III-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(III-1);

wherein V_(III-1), is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(III-1), substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N— ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituentoptionally having from one to nine fluorines;

wherein either R_(III-3) must contain V_(III) or R_(III-4) must containV_(III-1); and R_(III-5) and R_(III-6), or R_(III-6) and R_(III-7),and/or R_(III-7) and R_(III-8) are taken together and form at least onefour to eight membered ring that is partially saturated or fullyunsaturated optionally having one to three heteroatoms independentlyselected from nitrogen, sulfur and oxygen;

wherein said ring or rings formed by R_(III-5) and R_(III-6), orR_(III-6) and R_(III-7), and/or R_(III-7) and R_(III-8) are optionallymono-, di- or tri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent optionally having from one to nine fluorines;

provided that the R_(III-5), R_(III-6), R_(III-7) and/or R_(III-8), asthe case may be, that do not form at least one ring are eachindependently hydrogen, halo, (C₁-C₆)alkoxy or (C₁-C₆)alkyl, said(C₁-C₆)alkyl optionally having from one to nine fluorines.

Compounds of Formula III are disclosed in commonly assigned pending U.S.Pat. No. 6,147,089, the complete disclosure of which is hereinincorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula III:

-   [2R,    4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic    acid ethyl ester;-   [6R,    8S]8-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methyl-3,6,7,8-tetrahydro-1H-2-thia-5-aza-cyclopenta[b]naphthalene-5-carboxylic    acid ethylester;-   [6R,    8S]8-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methyl-3,6,7,8-tetrahydro-2H-furo[2,3-g]quinoline-5-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-3,4,6,8-tetrahydro-2H-furo[3,4-g]quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-3,4,6,7,8,9-hexahydro-2H-benzo[g]quinoline-1-carboxylic    acid propyl ester;-   [7R,9S]9-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methyl-1,2,3,7,8,9-hexahydro-6-aza-cyclopenta[a]naphthalene-6-carboxylic    acid ethyl ester; and-   [6S,8R]6-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-methyl-1,2,3,6,7,8-hexahydro-9-aza-cyclopenta[a]naphthalene-9-carboxylic    acid ethyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of4-carboxyamino-2-substituted-1,2,3,4,-tetrahydroquinolines, having theFormula IV

and pharmaceutically acceptable forms thereof;

wherein R_(IV-1) is hydrogen, Y_(IV), W_(IV)—X_(IV) or W_(IV)—Y_(IV);

wherein W_(IV) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_(IV) is —O—Y_(IV), —S—Y_(IV), —N(H)—Y_(IV) or —N—(Y_(IV))₂;

wherein Y_(IV) for each occurrence is independently Z_(IV) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(IV);

wherein Z_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(IV)substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

R_(IV-2) is a partially saturated, fully saturated or fully unsaturatedone to six membered straight or branched carbon chain wherein thecarbons, other than the connecting carbon, may optionally be replacedwith one or two heteroatoms selected independently from oxygen, sulfurand nitrogen wherein said carbon atoms are optionally mono-, di- ortri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R_(IV-2) is a partially saturated, fully saturated or fullyunsaturated three to seven membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,wherein said R_(IV-2) ring is optionally attached through (C₁-C₄)alkyl;

wherein said R_(IV-2) ring is optionally mono-, di- or tri-substitutedindependently with halo, (C₂-C₆)alkenyl, (C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, oxo or (C₁-C₆)alkyloxycarbonyl;

with the proviso that R_(IV-2) is not methyl;

R_(IV-13) is hydrogen or Q_(IV);

wherein Q_(IV) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(IV);

wherein V_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(IV) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N— or di-N,N—(C₁-C₆) alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

R_(IV-4) is Q_(IV-1) or V_(IV-1);

wherein Q_(IV-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(IV-1);

wherein V_(IV-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(IV-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N— ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

wherein either R_(IV-3) must contain V_(IV) or R_(IV-4) must containV_(IV-1);

R_(IV-5), R_(IV-6), R_(IV-7) and R_(IV-8) are each independentlyhydrogen, a bond, nitro or halo wherein said bond is substituted withT_(IV) or a partially saturated, fully saturated or fully unsaturated(C₁-C₁₂) straight or branched carbon chain wherein carbon, mayoptionally be replaced with one or two heteroatoms selectedindependently from oxygen, sulfur and nitrogen wherein said carbon atomsare optionally mono-, di- or tri-substituted independently with halo,said carbon is optionally mono-substituted with hydroxy, said carbon isoptionally mono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T_(IV);

wherein T_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(IV) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; and

wherein R_(IV-5) and R_(IV-6), or R_(IV-6) and R_(IV-7), and/or R_(IV-7)and R_(IV-8) may also be taken together and can form at least one fourto eight membered ring that is partially saturated or fully unsaturatedoptionally having one to three heteroatoms independently selected fromnitrogen, sulfur and oxygen;

wherein said ring or rings formed by R_(IV-5) and R_(IV-6), or R_(IV-6)and R_(IV-7), and/or R_(IV-7) and R_(IV-8) are optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; with the proviso that when R_(IV-2) is carboxyl or(C₁-C₄) alkylcarboxyl, then R_(IV-1) is not hydrogen.

Compounds of Formula IV are disclosed in commonly assigned U.S. Pat. No.6,197,786, the complete disclosure of which is herein incorporated byreference.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula IV:

-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]2-cyclopropyl-4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid tert-butyl ester;-   [2R,4R]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinaline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester,-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid 2-hydroxy-ethyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid propyl ester; and-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid propyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of 4-aminosubstituted-2-substituted-1,2,3,4,-tetrahydroquinolines, having theFormula V

and pharmaceutically acceptable forms thereof;

wherein R_(V-1), is Y_(V), W_(v)—X_(V) or W_(V)—Y_(V);

wherein W_(V) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_(V) is —O—Y_(V), —S—Y_(V), —N(H)—Y_(V) or —N—(Y_(V))₂;

wherein Y_(V) for each occurrence is independently Z_(V) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(V);

wherein Z_(V) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(V) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

R_(V-2) is a partially saturated, fully saturated or fully unsaturatedone to six membered straight or branched carbon chain wherein thecarbons, other than the connecting carbon, may optionally be replacedwith one or two heteroatoms selected independently from oxygen, sulfurand nitrogen wherein said carbon atoms are optionally mono-, di- ortri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R_(V-2) is a partially saturated, fully saturated or fullyunsaturated three to seven membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,wherein said R_(V-2) ring is optionally attached through (C₁-C₄)alkyl;

wherein said R_(V-2) ring is optionally mono-, di- or tri-substitutedindependently with halo, (C₂-C₆)alkenyl, (C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, oxo or (C₁-C₆)alkyloxycarbonyl;

R_(V-3) is hydrogen or Q_(V);

wherein Q_(V) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(V);

wherein V_(V) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(V) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N— or di-N,N—(C₁-C₆) alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

R_(V-4) is cyano, formyl, W_(V-1)Q_(V-1), W_(V-1)V_(V-1),(C₁-C₄)alkyleneV_(V-1) or V_(V-2);

wherein W_(V-1) is carbonyl, thiocarbonyl, SO or SO₂,

wherein Q_(V-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons may optionally be replaced with one heteroatomselected from oxygen, sulfur and nitrogen and said carbon is optionallymono-, di- or tri-substituted independently with halo, said carbon isoptionally mono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono-, ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with V_(V-1);

wherein V_(V-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(V-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,hydroxy, oxo, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N— ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

wherein V_(V-2) is a partially saturated, fully saturated or fullyunsaturated five to seven membered ring containing one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(V-2) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₂)alkyl, (C₁-C₂)alkoxy,hydroxy, or oxo wherein said (C₁-C₂)alkyl optionally has from one tofive fluorines; and

wherein R_(V-4) does not include oxycarbonyl linked directly to the C₄nitrogen;

wherein either R_(V-3) must contain V_(V) or R_(V-4) must containV_(V-1);

R_(V-5), R_(V-6), R_(V-7) and R_(V-8) are independently hydrogen, abond, nitro or halo wherein said bond is substituted with T_(V) or apartially saturated, fully saturated or fully unsaturated (C₁-C₁₂)straight or branched carbon chain wherein carbon may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen, wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with T_(V);

wherein T_(V) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(V) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent also optionally has from one to nine fluorines;

wherein R_(V-5) and R_(V-6), or R_(V-6) and R_(V-7), and/or R_(V-7) andR_(V-8) may also be taken together and can form at least one ring thatis a partially saturated or fully unsaturated four to eight memberedring optionally having one to three heteroatoms independently selectedfrom nitrogen, sulfur and oxygen;

wherein said rings formed by R_(V-5) and R_(V-6), or R_(V-6) andR_(V-7), and/or R_(V-7) and R_(V-8) are optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent also optionally has from one to nine fluorines.

Compounds of Formula V are disclosed in commonly assigned U.S. Pat. No.6,140,343, the complete disclosure of which is herein incorporated byreference.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula V:

-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid propyl ester;-   [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid tert-butyl ester;-   [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester,-   [2S,4S]4-[1-(3,5-bis-trifluoromethyl-benzyl)-ureido]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid propyl ester;-   [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester; and-   [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of cycloalkano-pyridines having the Formula VI

and pharmaceutically acceptable forms thereof;

in which A_(VI) denotes an aryl containing 6 to 10 carbon atoms, whichis optionally substituted with up to five identical or differentsubstituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy or a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in theform of a group according to the formula —NR_(VI-3)R_(VI-4), wherein

R_(VI-3) and R_(VI-4) are identical or different and denote a hydrogen,phenyl or a straight-chain or branched alkyl containing up to 6 carbonatoms,

D_(VI) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with a phenyl, nitro, halogen, trifluoromethyl ortrifluoromethoxy, or a radical according to the formulaR_(VI-5)-L_(VI)—,

or R_(VI-9)-T_(VI-—V) _(VI)—X_(VI), wherein

R_(VI-5), R_(VI-6) and R_(VI-9) denote, independently from one another,a cycloalkyl containing 3 to 6 carbon atoms, or an aryl containing 6 to10 carbon atom or a 5- to 7-membered, optionally benzo-condensed,saturated or unsaturated, mono-, bi- or tricyclic heterocycle containingup to 4 heteroatoms from the series of S, N and/or O, wherein the ringsare optionally substituted, in the case of the nitrogen-containing ringsalso via the N function, with up to five identical or differentsubstituents in the form of a halogen, trifluoromethyl, nitro, hydroxyl,cyano, carboxyl, trifluoromethoxy, a straight-chain or branched acyl,alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl containing up to6 carbon atoms each, an aryl or trifluoromethyl-substituted arylcontaining 6 to 10 carbon atoms each, or an optionally benzo-condensed,aromatic 5to 7-membered heterocycle containing up to 3 heteoatoms fromthe series of S, N and/or 0, and/or in the form of a group according tothe formula —OR_(VI-10), —SR_(VI-11), —SO₂R_(VI-12) or—NR_(VI-13)R_(VI-14), wherein

R_(VI-10), R_(VI-11) and R_(VI-12) denote, independently from oneanother, an aryl containing 6 to 10 carbon atoms, which is in turnsubstituted with up to two identical or different substituents in theform of a phenyl, halogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms,

R_(VI-13) and R_(VI-14) are identical or different and have the meaningof R_(VI-3) and R_(VI-4) given above, or

R_(VI-5) and/or R_(VI-6) denote a radical according to the formula

R_(VI-7) denotes a hydrogen or halogen, and

R_(VI-8) denotes a hydrogen, halogen, azido, trifluoromethyl, hydroxyl,trifluoromethoxy, a straight-chain or branched alkoxy or alkylcontaining up to 6 carbon atoms each, or a radical according to theformula—NR_(VI-15)R_(VI-16)wherein

R_(VI-15) and R_(VI-16) are identical or different and have the meaningof R_(VI-3) and R_(VI-4) given above, or

R_(VI-7) and R_(VI-8) together form a radical according to the formula═O or ═NR_(VI-17), wherein

R_(IV-17) denotes a hydrogen or a straight-chain or branched alkyl,alkoxy or acyl containing up to 6 carbon atoms each,

L_(VI) denotes a straight-chain or branched alkylene or alkenylene chaincontaining up to 8 carbon atoms each, which are optionally substitutedwith up to two hydroxyl groups,

T_(VI) and X_(VI) are identical or different and denote a straight-chainor branched alkylene chain containing up to 8 carbon atoms, or

T_(VI) or X_(VI) denotes a bond,

V_(VI) denotes an oxygen or sulfur atom or an —NR_(VI-18) group, wherein

R_(VI-18) denotes a hydrogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms or a phenyl,

E_(VI) denotes a cycloalkyl containing 3 to 8 carbon atoms, or astraight-chain or branched alkyl containing up to 8 carbon atoms, whichis optionally substituted with a cycloalkyl containing 3 to 8 carbonatoms or a hydroxyl, or a phenyl, which is optionally substituted with ahalogen or trifluoromethyl, R_(VI-1) and R_(VI-2) together form astraight-chain or branched alkylene chain containing up to 7 carbonatoms, which must be substituted with a carbonyl group and/or a radicalaccording to the formula

wherein

a and b are identical or different and denote a number equaling 1, 2 or3,

R_(VI-19) denotes a hydrogen atom, a cycloalkyl containing 3 to 7 carbonatoms, a straight-chain or branched silylalkyl containing up to 8 carbonatoms, or a straight-chain or branched alkyl containing up to 8 carbonatoms, which is optionally substituted with a hydroxyl, a straight-chainor a branched alkoxy containing up to 6 carbon atoms or a phenyl, whichmay in turn be substituted with a halogen, nitro, trifluoromethyl,trifluoromethoxy or phenyl or tetrazole-substituted phenyl, and an alkylthat is optionally substituted with a group according to the formula—OR_(VI-22), wherein

R_(VI-22) denotes a straight-chain or branched acyl containing up to 4carbon atoms or benzyl, or

R_(VI-19) denotes a straight-chain or branched acyl containing up to 20carbon atoms or benzoyl, which is optionally substituted with a halogen,trifluoromethyl, nitro or trifluoromethoxy, or a straight-chain orbranched fluoroacyl containing up to 8 carbon atoms,

R_(VI-20) and R_(VI-21) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms, or

R_(VI-20) and R_(VI-21) together form a 3- to 6-membered carbocyclicring, and a the carbocyclic rings formed are optionally substituted,optionally also geminally, with up to six identical or differentsubstituents in the form of trifluoromethyl, hydroxyl, nitrile, halogen,carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy containing 3to 7 carbon atoms each, a straight-chain or branched alkoxycarbonyl,alkoxy or alkylthio containing up to 6 carbon atoms each, or astraight-chain or branched alkyl containing up to 6 carbon atoms, whichis in turn substituted with up to two identical or differentsubstituents in the form of a hydroxyl, benzyloxy, trifluoromethyl,benzoyl, a straight-chain or branched alkoxy, oxyacyl or carboxylcontaining up to 4 carbon atoms each and/or a phenyl, which may in turnbe substituted with a halogen, trifluoromethyl or trifluoromethoxy,and/or the carbocyclic rings formed are optionally substituted, alsogeminally, with up to five identical or different substituents in theform of a phenyl, benzoyl, thiophenyl or sulfonylbenzyl, which in turnare optionally substituted with a halogen, trifluoromethyl,trifluoromethoxy or nitro, and/or optionally in the form of a radicalaccording to the formula

—SO₂—C₆H₅, —(CO)_(d)NR_(VI-23)R_(VI-24) or ═O,

wherein

c is a number equaling 1, 2, 3 or 4,

d is a number equaling 0 or 1,

R_(VI-23) and R_(VI- 24) are identical or different and denote ahydrogen, cycloalkyl containing 3 to 6 carbon atoms, a straight-chain orbranched alkyl containing up to 6 carbon atoms, benzyl or phenyl, whichis optionally substituted with up to two identical or differentsubstituents in the form of halogen, trifluoromethyl, cyano, phenyl ornitro, and/or the carbocyclic rings formed are optionally substitutedwith a spiro-linked radical according to the formula

wherein

W_(VI) denotes either an oxygen atom or a sulfur atom,

Y_(VI) and Y′_(VI) together form a 2- to 6-membered straight-chain orbranched alkylene chain,

e is a number equaling 1, 2, 3, 4, 5, 6 or 7,

f is a number equaling 1 or 2,

R_(VI-25), R_(VI-26), R_(VI-27), R_(VI-28), R_(VI-29), R_(VI-30) andR_(VI-31) are identical or different and denote a hydrogen,trifluoromethyl, phenyl, halogen or a straight-chain or branched alkylor alkoxy containing up to 6 carbon atoms each, or

R_(VI-25) and R_(VI-26) or R_(VI-27) and R_(VI-28) each together denotea straight-chain or branched alkyl chain containing up to 6 carbon atomsor

R_(VI-25) and R_(VI-26) or R_(VI-27) and R_(VI-28) each together form aradical according to the formula

wherein

W_(VI) has the meaning given above,

g is a number equaling 1, 2, 3, 4, 5, 6 or 7,

R_(VI-32) and R_(VI-33) together form a 3- to 7-membered heterocycle,which contains an oxygen or sulfur atom or a group according to theformula SO, SO₂ or —NR_(VI-34), wherein

R_(VI-34) denotes a hydrogen atom, a phenyl, benzyl, or a straight-chainor branched alkyl containing up to 4 carbon atoms, and salts and Noxides thereof, with the exception of 5(6H)-quinoiones,3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.

Compounds of Formula VI are disclosed in European Patent Application No.EP 818448 A1, the complete disclosure of which is herein incorporated byreference.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula VI:

-   2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-4,6,7,8-tetrahydro-1H-quinolin-5-one;-   2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-7,8-dihydro-6H-quinolin-5-one;-   [2-cyclopentyl-4-(4-fluorophenyl)-5-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanone;-   [5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanone;-   [5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanol;-   5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline;-   2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted-pyridines having the Formula VII

and pharmaceutically acceptable forms thereof, wherein

R_(VII-2) and R_(VII-6) are independently selected from the groupconsisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinatedaralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that atleast one of R_(VII-2) and R_(VII-6) is fluorinated alkyl,chlorofluorinated alkyl or alkoxyalkyl;

R_(VII-3) is selected from the group consisting of hydroxy, amido,arylcarbonyl, heteroarylcarbonyl, hydroxymethyl —CHO, —CO₂R_(VII-7),wherein R_(VII-7) is selected from the group consisting of hydrogen,alkyl and cyanoalkyl; and

wherein R_(VII-15a) is selected from the group consisting of hydroxy,hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy,heteroaryloxy and heterocyclyloxy, and

R_(VII-16), is selected from the group consisting of alkyl, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, andheterocyclyl, arylalkoxy, trialkylsilyloxy;

R_(VII-4) is selected from the group consisting of hydrogen, hydroxy,halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl,haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl,cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl,heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl,hetereoarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy,aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy,alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloyloxy,alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio,alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio,cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl,alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl,heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl,alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl,heterocyclythioalkenyl, alkylamino, alkenylamino, alkynylamino,arylamino, heteroarylamino, heterocyclylamino, aryldialkylamino,diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino,arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl,—CO(O)N(R_(VII-8a)R_(VII-8b)), wherein R_(VII-8a) and R_(VII-8b) areindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl, —SO₂R_(VII-9), whereinR_(VII-9) is selected from the group consisting of hydroxy, alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,—OP(O)(OR_(VII-10a)) (OR_(VII-10b)), wherein R_(VII-10a) andR_(VII-10b)are independently selected from the group consisting ofhydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl andheterocyclyl, and —OP(S) (OR_(VII-11)a) (OR_(VII-11b)), whereinR_(VII-11a) and R_(VII-11b) are independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl andheterocyclyl;

R_(VII-5) is selected from the group consisting of hydrogen, hydroxy,halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl,haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy,alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy,alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl,arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl,heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl,aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl,alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl,arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl,alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl,arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl,alkoxyalkyl, alkenoxyalkyl, alkynoxylalkyl, aryloxyalkyl,heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl,alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl,heterocyclyloxyalkenyl, cyano, hydroxymethyl, —CO₂R_(VII-14), whereinR_(VII-14) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl;

wherein R_(VII-15b) is selected from the group consisting of hydroxy,hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy,heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy, and

R_(VII-16b) is selected form the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, andtrialkylsilyloxy;

wherein R_(VII-17) and R_(VII-18) are independently selected from thegroup consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl and heterocyclyl;

wherein R_(VII-19) is selected from the group consisting of alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,—SR_(VII-20), —OR_(VII-21), and —R_(VII-22)CO₂R_(VII-23), wherein

R_(VII-20) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl,aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl,alkylheteroarylamino, arylheteroarylamino,

R_(VII-21) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl,

R_(VII-22) is selected from the group consisting of alkylene or arylene,and

R_(VII-23) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R_(VII-24) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, aralkenyl, and aralkynyl;

wherein R_(VII-25) is heterocyclylidenyl;

wherein R_(VII-26) and R_(VII-27) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

wherein R_(VII-28) and R_(VII-29) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

wherein R_(VII-30) and R_(VII-31) are independently alkoxy, alkenoxy,alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy; and

wherein R_(VII-32) and R_(VII-33) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

—C≡C—Si(R_(VII-36))₃

wherein R_(VII-36) is selected from the group consisting of alkyl,alkenyl, aryl, heteroaryl and heterocyclyl;

wherein R_(VII-37) and R_(VII-38) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

wherein R_(VII-39) is selected from the group consisting of hydrogen,alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy,alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio andheterocyclylthio, and

R_(VII-40) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl,cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy,heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio and heterocyclylthio;—N═R_(VII-41),

wherein R_(VII-41) is heterocyclylidenyl;

wherein R_(VII-42) is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and

R_(VII-43) is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl,haloheteroaryl, and haloheterocyclyl;

wherein R_(VII-44) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;—N═S═O;—N═C═S;—N═C═O;—N₃;—SR_(VII-45)

wherein R_(VII-45) is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl,heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl,heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl,alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl,heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl,alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl,heteroarylthioalkenyl, heterocyclylthioalkenyl, aminocarbonylalkyl,aminocarbonylalkenyl, aminocarbonylalkynyl, aminocarbonylaryl,aminocarbonylheteroaryl, and aminocarbonylheterocyclyl,—SR_(VII-46), and —CH₂R_(VII-47),

wherein R_(VII-46) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

R_(VII-47) is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; and

wherein R_(VII-48) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,and

R_(VII-49) is selected from the group consisting of alkoxy, alkenoxy,alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;

wherein R_(VII-50) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy;

wherein R_(VII-51) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;and

wherein R_(VII-53) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

provided that when R_(VII-5) is selected from the group consisting ofheterocyclylalkyl and heterocyclylalkenyl, the heterocyclyl radical ofthe corresponding heterocyclylalkyl or heterocyclylalkenyl is other thanδ-lactone; and

provided that when R_(VII-4) is aryl, heteroaryl or heterocyclyl, andone of R_(VII-2) and R_(VII-6) is trifluoromethyl, then the other ofR_(VII-2) and R_(VII-6) is difluoromethyl.

Compounds of Formula VII are disclosed in WO 9941237-A1, the completedisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula VII:

-   dimethyl    5,5′-dithiobis[2-difluoromethyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate].

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted pyridines and biphenyls having theFormula VIII

and pharmaceutically acceptable forms thereof,in which

A_(VIII) stands for aryl with 6 to 10 carbon atoms, which is optionallysubstituted up to 3 times in an identical manner or differently byhalogen, hydroxy, trifluoromethyl, trifluoromethoxy, or bystraight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula—NR_(VIII-1)R_(VIII-2), wherein

R_(VIII-1) and R_(VIII-2) are identical or different and denotehydrogen, phenyl, or straight-chain or branched alkyl with up to 6carbon atoms,

D_(VIII) stands for straight-chain or branched alkyl with up to 8 carbonatoms, which is substituted by hydroxy,

E_(VIII) and L_(VIII) are either identical or different and stand forstraight-chain or branched alkyl with up to 8 carbon atoms, which isoptionally substituted by cycloalkyl with 3 to 8 carbon atoms, or standsfor cycloalkyl with 3 to 8 carbon atoms, or

E_(VIII) has the above-mentioned meaning and

L_(VIII) in this case stands for aryl with 6 to 10 carbon atoms, whichis optionally substituted up to 3 times in an identical manner ordifferently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, orby straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula—NR_(VIII-3)R_(VIII-4), wherein

R_(VIII-3) and R_(VIII-4) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), or

E_(VIII) stands for straight-chain or branched alkyl with up to 8 carbonatoms, or stands for aryl with 6 to 10 carbon atoms, which is optionallysubstituted up to 3 times in an identical manner or differently byhalogen, hydroxy, trifluoromethyl, trifluoromethoxy, or bystraight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula—NR_(VIII-5)R_(VIII-6), wherein

R_(VIII-5) and R_(VIII-6) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), and

L_(VIII) in this case stands for straight-chain or branched alkoxy withup to 8 carbon atoms or for cycloalkyloxy with 3 to 8 carbon atoms,

T_(VIII) stands for a radical of the formula

wherein

R_(VIII-7) and R_(VIII-8) are identical or different and denotecycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms,or denote a 5- to 7-member aromatic, optionally benzo-condensed,heterocyclic compound with up to 3 heteroatoms from the series S, Nand/or O, which are optionally substituted up to 3 times in an identicalmanner or differently by trifluoromethyl, trifluoromethoxy, halogen,hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, oralkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy, orthiophenyl, which can in turn be substituted by halogen,trifluoromethyl, or trifluoromethoxy, and/or the rings are substitutedby a group of the formula—NR_(VIII-11)R_(VIII-12), wherein

R_(VIII-11) and R_(VIII-12) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2),

X_(VIII) denotes a straight or branched alkyl chain or alkenyl chainwith 2 to 10 carbon atoms each, which are optionally substituted up to 2times by hydroxy,

R_(VIII-9) denotes hydrogen, and

R_(VIII-10) denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy,mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to5 carbon atoms, or a radical of the formula—NR_(VIII-13)R_(VIII-14), wherein

R_(VIII-13) and R_(VIII-14) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), or

R_(VIII-9) and R_(VIII-10) form a carbonyl group together with thecarbon atom.

Compounds of Formula VIII are disclosed in WO 9804528, the completedisclosure of which is incorporated by reference.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted 1,2,4-triazoles having the Formula IX

and pharmaceutically acceptable forms thereof;

wherein R_(IX-1) is selected from higher alkyl, higher alkenyl, higheralkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl,arylthioalkyl, and cycloalkylalkyl;

wherein R_(IX-2) is selected from aryl, heteroaryl, cycloalkyl, andcycloalkenyl, wherein

R_(IX-2) is optionally substituted at a substitutable position with oneor more radicals independently selected from alkyl, haloalkyl,alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo, aryloxy,aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylamino anddialkylamino; and

wherein R_(IX-3) is selected from hydrido, —SH and halo; providedR_(IX-2) cannot be phenyl or 4-methylphenyl when R_(IX-1) is higheralkyl and when R_(IX-3) is —SH.

Compounds of Formula IX are disclosed in WO 9914204, the completedisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula IX:

-   2,4-dihydro-4-(3-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-fluorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   4-cyclohexyl-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-pyridyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-ethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2,6-dimethylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(4-phenoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   4-(1,3-benzodioxol-5-yl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   4-(2-chlorophenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(4-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-5-tridecyl-4-(3-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-5-tridecyl-4-(3-fluorophenyl)-3H-1,2,4-triazole-3-thione;-   4-(3-chloro-4-methylphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   4-(4-benzyloxyphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-naphthyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-5-tridecyl-4-(4-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(1-naphthyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(4-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3,4-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2,5-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-methoxy-5-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   4-(4-aminosulfonylphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-5-dodecyl-4-(3-methoxyphenyl)-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-methoxyphenyl)-5-tetradecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-methoxyphenyl)-5-undecyl-3H-1,2,4-triazole-3-thione;    and-   2,4-dihydro-(4-methoxyphenyl)-5-pentadecyl-3H-1,2,4-triazole-3-thione.

Another class of CETP inhibitors that finds utility with the presentinvention consists of hetero-tetrahydroquinolines having the Formula X

N-oxides of said compounds, and pharmaceutically acceptable formsthereof; in which

A_(X) represents cycloalkyl with 3 to 8 carbon atoms or a 5- to7-membered, saturated, partially saturated or unsaturated, optionallybenzo-condensed heterocyclic ring containing up to 3 heteroatoms fromthe series comprising S, N and/or 0, that in case of a saturatedheterocyclic ring is bonded to a nitrogen function, optionally bridgedover it, and in which the aromatic systems mentioned above areoptionally substituted up to 5-times in an identical or differentsubstituents in the form of halogen, nitro, hydroxy, trifluoromethyl,trifluoromethoxy or by a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy each having up to 7 carbon atoms or by a group ofthe formula —NR_(X-3)R_(X-4),

in which

R_(X-3) and R_(X-4) are identical or different and denote hydrogen,phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,

or

A_(X) represents a radical of the formula

D_(X) represents an aryl having 6 to 10 carbon atoms, that is optionallysubstituted by phenyl, nitro, halogen, trifluormethyl ortrifluormethoxy, or it represents a radical of the formula

in which

R_(X-5), R_(X-6) and R_(X-9) independently of one another denotecycloalkyl having 3 to 6 carbon atoms, or an aryl having 6 to 10 carbonatoms or a 5- to 7-membered aromatic, optionally benzo-condensedsaturated or unsaturated, mono-, bi-, or tricyclic heterocyclic ringfrom the series consisting of S, N and/or O, in which the rings aresubstituted, optionally, in case of the nitrogen containing aromaticrings via the N function, with up to 5 identical or differentsubstituents in the form of halogen, trifluoromethyl, nitro, hydroxy,cyano, carbonyl, trifluoromethoxy, straight straight-chain or branchedacyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl eachhaving up to 6 carbon atoms, by aryl or trifluoromethyl-substituted aryleach having 6 to 10 carbon atoms or by an, optionally benzo-condensed,aromatic 5- to 7-membered heterocyclic ring having up to 3 heteroatomsfrom the series consisting of S, N, and/or 0, and/or substituted by agroup of the formula —OR_(X-10), —SR_(X-11), SO₂R_(X-12) or—NR_(X-13)R_(X-14),

in which

R_(X-10), R_(X-11)and R_(X-12) independently from each other denote arylhaving 6 to 10 carbon atoms, which is in turn substituted with up to 2identical or different substituents in the form of phenyl, halogen or astraight-chain or branched alkyl having up to 6 carbon atoms,

R_(X-13) and R_(X-14) are identical or different and have the meaning ofR_(X-3) and R_(X-4) indicated above,

or

R_(X-5) and/or R_(X-6) denote a radical of the formula

R_(X-7)denotes hydrogen or halogen, and

R_(X-8) denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy,trifluoromethoxy, straight-chain or branched alkoxy or alkyl having upto 6 carbon atoms or a radical of the formula —NR_(X-15)R_(X-16), inwhich

R_(X-15) and R_(X-16) are identical or different and have the meaning ofR_(X-3) and R_(X-4) indicated above,

or

R_(X-7) and R_(X-8) together form a radical of the formula ═O or═NR_(X-17), in which

R_(X-17) denotes hydrogen or straight chain or branched alkyl, alkoxy oracyl having up to 6 carbon atoms,

L_(X) denotes a straight chain or branched alkylene or alkenylene chainhaving up to 8 carbon atoms, that are optionally substituted with up to2 hydroxy groups,

T_(x) and X_(x) are identical or different and denote a straight chainor branched alkylene chain with up to 8 carbon atoms

or

T_(x) or X_(x) denotes a bond,

V_(x) represents an oxygen or sulfur atom or an —NR_(X-18)-group, inwhich

R_(X-18) denotes hydrogen or straight chain or branched alkyl with up to6 carbon atoms or phenyl,

E_(x) represents cycloalkyl with 3 to 8 carbon atoms, or straight chainor branched alkyl with up to 8 carbon atoms, that is optionallysubstituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy, orrepresents a phenyl, that is optionally substituted by halogen ortrifluoromethyl,

R_(X-1) and R_(X-2) together form a straight-chain or branched alkylenechain with up to 7 carbon atoms, that must be substituted by carbonylgroup and/or by a radical with the formula

in which a and b are identical or different and denote a number equaling1,2, or 3,

R_(X-19) denotes hydrogen, cycloalkyl with 3 up to 7 carbon atoms,straight chain or branched silylalkyl with up to 8 carbon atoms orstraight chain or branched alkyl with up to 8 carbon atoms, that areoptionally substituted by hydroxyl, straight chain or branched alkoxywith up to 6 carbon atoms or by phenyl, which in turn might besubstituted by halogen, nitro, trifluormethyl, trifluoromethoxy or byphenyl or by tetrazole-substituted phenyl, and alkyl, optionally besubstituted by a group with the formula —OR_(X-22),

in which

R_(X-22) denotes a straight chain or branched acyl with up to 4 carbonatoms or benzyl,

or

R_(X-19) denotes straight chain or branched acyl with up to 20 carbonatoms or benzoyl, that is optionally substituted by halogen,trifluoromethyl, nitro or trifluoromethoxy, or it denotes straight chainor branched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,

R_(X-20) and R_(X-21) are identical or different and denote hydrogen,phenyl or straight chain or branched alkyl with up to 6 carbon atoms,

or

R_(X-20) and R_(X-21) together form a 3- to 6-membered carbocyclic ring,and the carbocyclic rings formed are optionally substituted, optionallyalso geminally, with up to six identical or different substituents inthe form of triflouromethyl, hydroxy, nitrile, halogen, carboxyl, nitro,azido, cyano, cycloalkyl or cycloalkyloxy with 3 to 7 carbon atoms each,by straight chain or branched alkoxycarbonyl, alkoxy or alkylthio withup to 6 carbon atoms each or by straight chain or branched alkyl with upto 6 carbon atoms, which in turn is substituted with up to 2 identicallyor differently by hydroxyl, benzyloxy, trifluoromethyl, benzoyl,straight chain or branched alkoxy, oxyacyl or carbonyl with up to 4carbon atoms each and/or phenyl, which may in turn be substituted with ahalogen, trifuoromethyl or trifluoromethoxy, and/or the formedcarbocyclic rings are optionally substituted, also geminally, with up to5 identical or different substituents in the form of phenyl, benzoyl,thiophenyl or sulfonylbenzyl, which in turn are optionally substitutedby halogen, trifluoromethyl, trifluoromethoxy or nitro, and/oroptionally are substituted by a radical with the formula

—SO₂—C₆H₅, —(CO)_(d)NR_(X-23)R_(X-24) or ═O,

in which

c denotes a number equaling 1, 2, 3, or 4,

d denotes a number equaling 0 or 1,

R_(X-23) and R_(X-24) are identical or different and denote hydrogen,cycloalkyl with 3 to 6 carbon atoms, straight chain or branched alkylwith up to 6 carbon atoms, benzyl or phenyl, that is optionallysubstituted with up to 2 identically or differently by halogen,trifluoromethyl, cyano, phenyl or nitro, and/or the formed carbocyclicrings are substituted optionally by a spiro-linked radical with theformula

in which

W_(x) denotes either an oxygen or a sulfur atom

Y_(x) and Y′_(x) together form a 2 to 6 membered straight chain orbranched alkylene chain,

e denotes a number equaling 1, 2, 3, 4, 5, 6, or 7,

f denotes a number equaling 1 or 2,

R_(X-25), R_(X-26), R_(X-27), R_(X-28), R_(X-29), R_(X-30) and R_(X-31)are identical or different and denote hydrogen, trifluoromethyl, phenyl,halogen or straight chain or branched alkyl or alkoxy with up to 6carbon atoms each,

or

R_(X-25) and R_(X-26) or R_(X-27) and R_(X-28) respectively formtogether a straight chain or branched alkyl chain with up to 6 carbonatoms,

or

R_(X-25) and R_(X-26) or R_(X-27) and R_(X-28) each together form aradical with the formula

in which

W_(X) has the meaning given above, g denotes a number equaling 1, 2, 3,4, 5, 6, or 7,

R_(X-32) and R_(X-33) form together a 3- to 7-membered heterocycle,which contains an oxygen or sulfur atom or a group with the formula SO,SO₂ or π-NR_(X-34), in which

R_(X-34) denotes hydrogen, phenyl, benzyl or straight or branched alkylwith up to 4 carbon atoms.

Compounds of Formula X are disclosed in WO 9914215, the completedisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula X:

-   2-cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(4-trifluoromethylbenxoyl)-5,6,7,8-tetrahydroquinoline;-   2-cyclopentyl-3-[fluoro-(4-trifluoromethylphenyl)methyl]-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-5,6,7,8-tetrahydroquinoline;    and-   2-cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(trifluoromethylbenxyl)-5,6,7,8-tetrahydroquinoline.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted tetrahydro naphthalines and analogouscompounds having the Formula XI

and pharmaceutically acceptable forms thereof, in which

A_(XI) stands for cycloalkyl with 3 to 8 carbon atoms, or stands foraryl with 6 to 10 carbon atoms, or stands for a 5- to 7-membered,saturated, partially unsaturated or unsaturated, possiblybenzocondensated, heterocycle with up to 4 heteroatoms from the seriesS, N and/or O, where aryl and the heterocyclic ring systems mentionedabove are substituted up to 5-fold, identical or different, by cyano,halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoro-methoxy,or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio,alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each with up to 7 carbonatoms, or by a group of the formula—NR_(XI-3)R_(XI-4),in which

R_(XI-3) and R_(XI-4) are identical or different and denote hydrogen,phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms

D_(XI) stands for a radical of the formula

in which

R_(XI-5), R_(XI-6) and R_(XI-9), independent of each other, denotecycloalkyl with 3to 6 carbon atoms, or denote aryl with 6 to 10 carbonatoms, or denote a 5- to 7-membered, possibly benzocondensated,saturated or unsaturated, mono-, bi- or tricyclic heterocycle with up to4 heteroatoms of the series S, N and/or O, where the cycles are possiblysubstituted-in the case of the nitrogen-containing rings also via theN-function-up to 5-fold, identical or different, by halogen,trifluoromethyl, nitro, hydroxy, cyano, carboxyl, trifluoromethoxy,straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl with up to 6 carbon atoms each by aryl ortrifluoromethyl substituted aryl with 6 to 10 carbon atoms each, or by apossibly benzocondensated aromatic 5- to 7-membered heterocycle with upto 3 heteroatoms of the series S, N and/or O, and/or are substituted bya group of the formula—OR_(XI-10), —SR_(XI-11), —SO₂R_(XI-12) or —NR_(XI-13)R_(XI-14),in which

R_(XI-10), R_(XI-11) and R_(XI-12), independent of each other, denotearyl with 6 to 10 carbon atoms, which itself is substituted up to2-fold, identical or different, by phenyl, halogen or by straight-chainor branched alkyl with up to 6 carbon atoms,

R_(XI-13) and R_(XI-14) are identical or different and have the meaninggiven above for R_(XI-3) and R_(XI-4),

or

R_(XI-5) and/or R_(XI-)6 denote a radical of the formula

R_(XI-7) denotes hydrogen, halogen or methyl,

and

R_(XI-8) denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy,trifluoromethoxy, straight-chain or branched alkoxy or alkyl with up to6 carbon atoms each, or a radical of the formula —NR_(XI-15)R_(XI-16),

in which

R_(XI-15) and R_(XI-16) are identical or different and have the meaninggiven above for R_(XI-3) and R_(XI-4),

or

R_(XI-7) and R_(XI-6) together form a radical of the formula ═O or═NR_(XI-17), in which

R_(XI-17) denotes hydrogen or straight-chain or branched alkyl, alkoxyor acyl with up to 6 carbon atoms each,

L_(XI) denotes a straight-chain or branched alkylene- or alkenylenechain with up to 8 carbon atoms each, which is possibly substituted upto 2-fold by hydroxy,

T_(XI) and X_(XI) are identical or different and denote a straight-chainor branched alkylene chain with up to 8 carbon atoms,

or

T_(XI) and X_(XI) denotes a bond,

V_(XI) stands for an oxygen- or sulfur atom or for an —NR_(XI-18) group,in which

R_(XI-18) denotes hydrogen or straight-chain or branched alkyl with upto 6 carbon atoms, or phenyl,

E_(XI) stands for cycloalkyl with 3 to 8 carbon atoms, or stands forstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy,or stands for phenyl, which is possibly substituted by halogen ortrifluoromethyl,

R_(XI-1) and R_(XI-2) together form a straight-chain or branchedalkylene chain with up to 7 carbon atoms, which must be substituted by acarbonyl group and/or by a radical of the formula

in which

a and b are identical or different and denote a number 1, 2 or 3

R_(XI-19) denotes hydrogen, cycloalkyl with 3 to 7 carbon atoms,straight-chain or branched silylalkyl with up to 8 carbon atoms, orstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by hydroxy, straight-chain or branched alkoxy withup to 6 carbon atoms, or by phenyl, which itself can be substituted byhalogen, nitro, trifluoromethyl, trifluoromethoxy or by phenylsubstituted by phenyl or tetrazol, and alkyl is possibly substituted bya group of the formula —OR_(XI-22),

in which

R_(XI-22) denotes straight-chain or branched acyl with up to 4 carbonatoms, or benzyl,

or

R_(XI-19) denotes straight-chain or branched acyl with up to 20 carbonatoms or benzoyl, which is possibly substituted by halogen,trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain orbranched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,

R_(XI-20) and R_(XI-21) are identical or different, denoting hydrogen,phenyl or straight-chain or branched alkyl with up to 6 carbon atoms,

or

R_(XI-20) and R_(XI-21) together form a 3- to 6-membered carbocycle,and, possibly also geminally, the alkylene chain formed by R_(XI-1) andR_(XI-2), is possibly substituted up to 6-fold, identical or different,by trifluoromethyl, hydroxy, nitrile, halogen, carboxyl, nitro, azido,cyano, cycloalkyl or cycloalkyloxy with 3 to 7 carbon atoms each, bystraight-chain or branched alkoxycarbonyl, alkoxy or alkoxythio with upto 6 carbon atoms each, or by straight-chain or branched alkyl with upto 6 carbon atoms, which itself is substituted up to 2-fold, identicalor different, by hydroxyl, benzyloxy, trifluoromethyl, benzoyl,straight-chain or branched alkoxy, oxyacyl or carboxyl with up to 4carbon atoms each, and/or phenyl—which itself can be substituted byhalogen, trifluoromethyl or trifluoromethoxy, and/or the alkylene chainformed by R_(XI-1) and R_(XI-2) is substituted, also geminally, possiblyup to 5-fold, identical or different, by phenyl, benzoyl, thiophenyl orsulfobenzyl—which themselves are possibly substituted by halogen,trifluoromethyl, trifluoromethoxy or nitro, and/or the alkylene chainformed by R_(XI-1) and R_(XI-2) is possibly substituted by a radical ofthe formula

—SO₂—C₆H₅, —(CO)_(d)NR_(XI-23)R_(XI-24) or ═O,

in which

c denotes a number 1, 2, 3 or 4,

d denotes a number 0 or 1,

R_(XI-23) and R_(XI-24) are identical or different and denote hydrogen,cycloalkyl with 3 to 6 carbon atoms, straight-chain or branched alkylwith up to 6 carbon atoms, benzyl or phenyl, which is possiblysubstituted up to 2-fold identical or different, by halogen,trifluoromethyl, cyano, phenyl or nitro, and/or the alkylene chainformed by R_(XI-1) and R_(XI-2) is possibly substituted by aspiro-jointed radical of the formula

in which

W_(XI) denotes either an oxygen or a sulfur atom,

Y_(XI) and Y′_(XI) together form a 2- to 6-membered straight-chain orbranched alkylene chain,

e is a number 1, 2, 3, 4, 5, 6 or 7,

f denotes a number 1 or 2,

R_(XI-25), R_(XI-26), R_(XI-27), R_(XI-28), R_(XI-29), R_(XI-30) andR_(XI-31) are identical or different and denote hydrogen,trifluoromethyl, phenyl, halogen, or straight-chain or branched alkyl oralkoxy with up to 6 carbon atoms each,

or

R_(XI-25) and R_(XI-26) or R_(XI-27) and R_(XI-28) together form astraight-chain or branched alkyl chain with up to 6 carbon atoms,

or

R_(XI-25) and R_(XI-26) or R_(XI-27) and R_(XI-28) together form aradical of the formula

in which

W_(XI) has the meaning given above,

g is a number 1, 2, 3, 4, 5, 6 or 7,

R_(XI-32) and R_(XI-33) together form a 3- to 7-membered heterocyclethat contains an oxygen- or sulfur atom or a group of the formula SO,SO₂ or —NR_(XI-34),

in which R_(XI-34) denotes hydrogen, phenyl, benzyl, or straight-chainor branched alkyl with up to 4 carbon atoms.

Compounds of Formula XI are disclosed in WO 9914174, the completedisclosure of which is incorporated by reference.

Another class of CETP inhibitors that finds utility with the presentinvention consists of 2-aryl-substituted pyridines having the FormulaXII

and pharmaceutically acceptable forms thereof, in which

A_(XII) and E_(XII) are identical or different and stand for aryl with 6to 10 carbon atoms which is possibly substituted, up to 5-fold identicalor different, by halogen, hydroxy, trifluoromethyl, trifluoromethoxy,nitro or by straight-chain or branched alkyl, acyl, hydroxy alkyl oralkoxy with up to 7 carbon atoms each, or by a group of the formula—NR_(XII-1)R_(XII-2),

where

R_(XII) and R_(XII-2) are identical or different and are meant to behydrogen, phenyl or straight-chain or branched alkyl with up to 6 carbonatoms,

D_(XII) stands for straight-chain or branched alkyl with up to 8 carbonatoms, which is substituted by hydroxy,

L_(XII) stands for cycloalkyl with 3 to 8 carbon atoms or forstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by cycloalkyl with 3 to 8 carbon atoms, or byhydroxy,

T_(XII) stands for a radical of the formula R_(XII-3)—X_(XII)— or

where

R_(XII-3) and R_(XII-4) are identical or different and are meant to becycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms,or a 5- to 7-membered aromatic, possibly benzocondensated heterocyclewith up to 3 heteroatoms from the series S, N and/or O, which arepossibly substituted up to 3-fold identical or different, bytrifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, nitro, bystraight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl with upto 6 carbon atoms each or by phenyl, phenoxy or phenylthio which in turncan be substituted by halogen trifluoromethyl or trifluoromethoxy,and/or where the cycles are possibly substituted by a group of theformula —NR_(XII-7)R_(XII-8),

where

R_(XII-7) and R_(XII-8) are identical or different and have the meaningof R_(XII-1) and R_(XII-2) given above,

X_(XII) is a straight-chain or branched alkyl or alkenyl with 2 to 10carbon atoms each, possibly substituted up to 2-fold by hydroxy orhalogen,

R_(XII-5) stands for hydrogen,

and

R_(XII-6) means to be hydrogen, halogen, mercapto, azido,trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branchedalkoxy with up to 5 carbon atoms, or a radical of the formula—NR_(XII-9)R_(XII-10),

where

R_(XII-9) and R_(XII-10) are identical or different and have the meaningof R_(XII-1) and R_(XII-2) given above,

or

R_(XII-5) and R_(XII-6), together with the carbon atom, form a carbonylgroup.

Compounds of Formula XII are disclosed in EP 796846-A1, the completedisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XII:

-   4,6-bis-(p-fluorophenyl)-2-isopropyl-3-[(p-trifluoromethylphenyl)-(fluoro)-methyl]-5-(1-hydroxyethyl)pyridine;-   2,4-bis-(4-fluorophenyl)-6-isopropyl-5-[4-(trifluoromethylphenyl)-fluoromethyl]-3-hydroxymethyl)pyridine;    and-   2,4-bis-(4-fluorophenyl)-6-isopropyl-5-[2-(3-trifluoromethylphenyl)vinyl]-3-hydroxymethyl)pyridine.

Another class of CETP inhibitors that finds utility with the presentinvention consists of compounds having the Formula XIII

and pharmaceutically acceptable forms thereof, in which

R_(XII) is a straight chain or branched C₁₋₁₀ alkyl; straight chain orbranched C₂₋₁₀ alkenyl; halogenated C₁₋₄ lower alkyl; C₃₋₁₀ cycloalkylthat may be substituted; C₅₋₈ cycloalkenyl that may be substituted;C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl that may be substituted; aryl that may besubstituted; aralkyl that may be substituted; or a 5- or 6-memberedheterocyclic group having 1 to 3 nitrogen atoms, oxygen atoms or sulfuratoms that may be substituted,

X_(XIII-1), X_(XIII-2), X_(XIII-3), X_(XIII-4) may be the same ordifferent and are a hydrogen atom; halogen atom; C₁₋₄ lower alkyl;halogenated C₁₋₄ lower alkyl; C₁₋₄ lower alkoxy; cyano group; nitrogroup; acyl; or aryl, respectively;

Y_(XIII) is —CO—; or —SO₂—; and

Z_(XIII) is a hydrogen atom; or mercapto protective group.

Compounds of Formula XII are disclosed in WO 98/35937, the completedisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XIII:

-   N,N′-(dithiodi-2,1-phenylene)bis[2,2-dimethyl-propanamide];-   N,N′-(dithiodi-2,1-phenylene)bis[1-methyl-cyclohexanecarboxamide];-   N,N′-(dithiodi-2,1-phenylene)bis[1-(3-methylbutyl)-cyclopentanecarboxamide];-   N,N′-(dithiodi-2,1-phenylene)bis[1-(3-methylbutyl)-cyclohexanecarboxamide];-   N,N′-(dithiodi-2,1-phenylene)bis[1-(2-ethylbutyl)-cyclohexanecarboxamide];-   N,N′-(dithiodi-2,1-phenylene)bis-tricyclo[3.3.1.1^(3,7)]decane-1-carboxamide;-   propanethioic acid,    2-methyl-,S-[2[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]ester;-   propanethioic acid, 2,2-dimethyl-,    S-[2-[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]ester; and-   ethanethioic acid,    S-[2-[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of polycyclic aryl and heteroaryltertiary-heteroalkylamines having the Formula XIV

and pharmaceutically acceptable forms thereof, wherein:

n_(XIV) is an integer selected from 0 through 5;

R_(XIV-I) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;

X_(XIV) is selected from the group consisting of O, H, F, S, S(O),NH,N(OH), N(alkyl), and N(alkoxy);

R_(XIV-1) ₆ is selected from the group consisting of hydrido, alkyl,alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl,halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl,monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl,dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl,heteroaryloxyalkyl, dialkoxyphosphonoalkyl, trialkylsilyl, and a spacerselected from the group consisting of a covalent single bond and alinear spacer moiety having from 1 through 4 contiguous atoms linked tothe point of bonding of an aromatic substituent selected from the groupconsisting of R_(XIV-4), R_(XIV-8), R_(XIV-9), and R_(XIV-13) to form aheterocyclyl ring having from 5 through 10 contiguous members with theprovisos that said spacer moiety is other than a covalent single bondwhen R_(XIV-2) is alkyl and there is no R_(XIV-16) wherein X is H or F;

D_(XIV-1), D_(XIV-2) J_(XIV-1), J_(XIV-2) and K_(XIV-1) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XIV-1),D_(XIV-2), J_(XIV-1) J_(XIV-2) and K_(XIV-1) is a covalent bond, no morethan one of D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) is0, no more than one of D_(XIV-1) D_(XIV-2), J_(XIV-1), J_(XIV-2) andK_(XIV-1) is S, one of D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) andK_(XIV-1) must be a covalent bond when two of D_(XIV-1), J_(XIV-1),J_(XIV-2) and K_(XIV-1) are O and S, and no more than four of D_(XIV-1),D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) are N;

D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-)4 and K_(XIV-2) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XIV-3),D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) is a covalent bond, nomore than one of D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) andK_(XIV-2) is 0, no more than one of D_(XIV-3), D_(XIV-)4, J_(XIV-3),J_(XIV-4) and K_(XIV-2) is S, one of D_(XIV-3), D_(XIV-4), J_(XIV-3),J_(XIV-)4 and K_(XIV-2) must be a covalent bond when two of D_(XIV-3),D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) are O and S, and no morethan four of D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2)and K_(XIV-2) are N;

R_(XIV-2) is independently selected from the group consisting ofhydrido, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino,dialkylamino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,aloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, alkylsulfinylalkyl, alkylsulfonylalkyl,haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl,arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl,cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl,cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl,heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl,aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide,carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

R_(XIV-2) and R_(XIV-3 are) taken together to form a linear spacermoiety selected from the group consisting of a covalent single bond anda moiety having from 1 through 6 contiguous atoms to form a ringselected from the group consisting of a cycloalkyl having from 3 through8 contiguous members, a cycloalkenyl having from 5 through 8 contiguousmembers, and a heterocyclyl having from 4 through 8 contiguous members;

R_(XIV-3 is) selected from the group consisting of hydrido, hydroxy,halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamino, dialkylamino,acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl,alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,heteroarylthio, aralkylthio, aralkoxyalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl,heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl,haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl,monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl,alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl,arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl,aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl,cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy; carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

Y_(XIV) is selected from a group consisting of a covalent single bond,(C(R_(XIV-14))₂)_(qXIV) wherein _(qXIV) is an integer selected from 1and 2 and (CH(R_(XIV-14)))_(gXIV)—W_(XIV)—(CH(R_(XIV-14)))_(pXIV)wherein _(gXIV) and _(pXIV) are integers independently selected from 0and 1;

R_(XIV-14) is independently selected from the group consisting ofhydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino,hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl,acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl,aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl,alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-9) and R_(XIV-13)to form a ring selected from the group consisting of a cycloalkenyl ringhaving from 5 through 8 contiguous members and a heterocyclyl ringhaving from 5 through 8 contiguous members and a spacer selected from amoiety having a chain length of 2 to 5 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-4) and R_(XIV-8) toform a heterocyclyl having from 5 through 8 contiguous members with theproviso that, when Y_(XIV) is a covalent bond, an R_(XIV-14) substituentis not attached to Y_(XIV);

R_(XIV-14) and R_(XIV-14), when bonded to the different atoms, are takentogether to form a group selected from the group consisting of acovalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

R_(XIV-14) and R_(XIV-14), when bonded to the same atom are takentogether to form a group selected from the group consisting of oxo,thiono, alkylene, haloalkylene, and a spacer selected from the groupconsisting of a moiety having a chain length of 3 to 7 atoms connectedto form a ring selected from the group consisting of a cycloalkyl havingfrom 4 through 8 contiguous members, a cycloalkenyl having from 4through 8 contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

W_(XIV) is selected from the group consisting of O, C(O), C(S),C(O)N(R_(XIV-14)), C(S)N(R_(XIV-14)), (R_(XIV-14))NC(O),(R_(XIV-14))NC(S), S, S(O), 5(O)₂, S(O)₂N(R_(XIV-14)),(R_(XIV-14))NS(O)₂, and N(R_(XIV-14)) with the proviso that R_(XIV-14)is selected from other than halo and cyano;

Z_(XIV) is independently selected from a group consisting of a covalentsingle bond, (C(R_(XIV-15))₂)_(qXIV-2) wherein _(qXIV-2) is an integerselected from 1 and 2, (CH(R_(XIV-15)))_(jXIV)—W—(CH(R_(XIV-15)))_(kXIV)wherein _(jXIV) and _(kXIV) are integers independently selected from 0and 1 with the proviso that, when Z_(XIV) is a covalent single bond, anR_(XIV-15)substituent is not attached to Z_(XIV);

R_(XIV-15) is independently selected, when Z_(XIV) is(C(R_(XIV-15))₂)_(qXIV) wherein _(qXIV) is an integer selected from 1and 2, from the group consisting of hydrido, hydroxy, halo, cyano,aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl,heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy,alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl,heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-4) and R_(XIV-8) toform a ring selected from the group consisting of a cycloalkenyl ringhaving from 5 through 8 contiguous members and a heterocyclyl ringhaving from 5 through 8 contiguous members, and a spacer selected from amoiety having a chain length of 2 to 5 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-9) and R_(XIV-13)to form a heterocyclyl having from 5 through 8 contiguous members;

R_(XIV-15) and R_(XIV-15), when bonded to the different atoms, are takentogether to form a group selected from the group consisting of acovalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

R_(XIV-15) and R_(XIV-15), when bonded to the same atom are takentogether to form a group selected from the group consisting of oxo,thiono, alkylene, haloalkylene, and a spacer selected from the groupconsisting of a moiety having a chain length of 3 to 7 atoms connectedto form a ring selected from the group consisting of a cycloalkyl havingfrom 4 through 8 contiguous members, a cycloalkenyl having from 4through 8 contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

R_(XIV-15) is independently selected, when Z_(XIV) is(CH(R_(XIV-15)))_(jXIV)—W—(CH(R_(XIV-15)))_(kXIV) wherein _(jXIV) and_(kXIV) are integers independently selected from 0 and 1, from the groupconsisting of hydrido, halo, cyano, aryloxy, carboxyl, acyl, aroyl,heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy,alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl,arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl,aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma linear moiety having a chain length of 3 to 6 atoms connected to thepoint of bonding selected from the group consisting of R_(XIV-4) andR_(XIV-8) to form a ring selected from the group consisting of acycloalkenyl ring having from 5 through 8 contiguous members and aheterocyclyl ring having from 5 through 8 contiguous members, and aspacer selected from a linear moiety having a chain length of 2 to 5atoms connected to the point of bonding selected from the groupconsisting of R_(XIV-g) and R_(XIV-13) to form a heterocyclyl ringhaving from 5 through 8 contiguous members;

R_(XIV-4), R_(XIV-5), R_(XIV-6) R_(XIV-7), R_(XIV-8), R_(XIV-9),R_(XIV-10), R_(XIV-11), R_(XIV-12), and R_(XIV-13) are independentlyselected from the group consisting of perhaloaryloxy, alkanoylalkyl,alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy,heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy,alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy,aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido,N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl,cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio,heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy,heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl, amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl; haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that there are one to fivenon-hydrido ring substituents R_(XIV-4), R_(XIV-5), R_(XIV-6),R_(XIV-7), and R_(XIV-8) present, that there are one to five non-hydridoring substituents R_(XIV-9), R_(XIV-10), R_(XIV-11), R_(XIV-12), andR_(XIV-13) present, and R_(XIV-4), R_(XIV-5), R_(XIV-6), R_(XIV-7),R_(XIV-8), R_(XIV-9), R_(XIV-10), R_(XIV-11), R_(XIV-12), and R_(XIV-13)are each independently selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

R_(XIV-4) and R_(XIV-5), R_(XIV-5) and R_(XIV-6), R_(XIV-6) andR_(XIV-7), R_(XIV-7) and R_(XIV-8), R_(XIV-8) and R_(XIV-9), R_(XIV-9)and R_(XIV-10), R_(XIV-10) and R_(XIV-11), R_(XIV-11) and R_(XIV-12),and R_(XIV-12) and R_(XIV-13) are independently selected to form spacerpairs wherein a spacer pair is taken together to form a linear moietyhaving from 3 through 6 contiguous atoms connecting the points ofbonding of said spacer pair members to form a ring selected from thegroup consisting of a cycloalkenyl ring having 5 through 8 contiguousmembers, a partially saturated heterocyclyl ring having 5 through 8contiguous members, a heteroaryl ring having 5 through 6 contiguousmembers, and an aryl with the provisos that no more than one of thegroup consisting of spacer pairs R_(XIV)4 and R_(XIV-5), R_(XIV-5) andR_(XIV-6), R_(XIV and Rx) _(XIV-7), and R_(XIV-7) and R_(XIV-8) are usedat the same time and that no more than one of the group consisting ofspacer pairs R_(XIV-9) and R_(XIV-10), R_(XIV-10) and R_(XIV-11, R)_(XIV-11) and R_(XIV-12), and R_(XIV-12) and R_(XIV-13) are used at thesame time;

R_(XIV-4) and R_(XIV-9), R_(XIV-4) and R_(XIV-13), R_(XIV-8) andR_(XIV-9), and R_(XIV-8) and R_(XIV-13) are independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear moiety wherein said linear moiety forms a ring selected from thegroup consisting of a partially saturated heterocyclyl ring having from5 through 8 contiguous members and a heteroaryl ring having from 5through 6 contiguous members with the proviso that no more than one ofthe group consisting of spacer pairs R_(XIV-4) and R_(XIV-9), R_(XIV-4)and R_(XIV-13), R_(XIV-8) and R_(XIV-9), and R_(XIV-8) and R_(XIV-13) isused at the same time.

Compounds of Formula XIV are disclosed in WO 00/18721, the entiredisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XIV:

-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-methlylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-l    1,1-trifluoro-2-propanol;-   3-[[3-(3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-t-butylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]    1,1,1-trifluoro-2-propanol;-   3-[[3-(3-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,11,-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(pentafluoroethymethyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-11,1,1-trifluoro-2-propanol;-   3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-t-butylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-methylphenoxy)phenyl][[3-pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,-trifluoro-2-propanol;-   3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-30    methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,11-trifluoro-2-propanol;-   3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,-trifluoro-2-propanol;-   3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;    3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafluoropropyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-4-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;    and-   3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substitued N-Aliphatic-N-Aromatictertiary-Heteroalkylamines having the Formula XV

and pharmaceutically acceptable forms thereof, wherein:

n_(XV) is an integer selected from 1 through 2;

A_(XV) and Q_(XV) are independently selected from the group consistingof —CH₂(CR_(XV-37)R_(XV-38))_(vXV)—(CR_(XV-33)R_(XV-34))_(uXV-T)_(XV)—(CR_(XV-35)R_(XV-36))_(wXV—)H,

with the provisos that one of A_(XV) and Q_(XV) must be AQ-1 and thatone of A_(XV) and Q_(XV) must be selected from the group consisting ofAQ-2 and—CH₂(CR_(XV-37)R_(XV-38))_(vXV)—(CR_(XV-33)R_(XV-34))_(uXV)-T_(XV)—(CR_(XV-35)R_(XV-36))_(wXV)—H;

T_(XV) is selected from the group consisting of a single covalent bond,O, S, S(O), S(O)₂, C(R_(XV-33))═C(R_(XV-35)), and

C≡C;

_(vXV) is an integer selected from 0 through 1 with the proviso that_(vXV) is 1 when any one of R_(XV-33), R_(XV-34), R_(XV-35), andR_(XV-36) is aryl or heteroaryl;

_(uXV) and _(wXV) are integers independently selected from 0 through 6;

A_(XV-l) is C(R_(XV-30));

D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1), are independentlyselected from the group consisting of C, N, O, S and a covalent bondwith the provisos that no more than one of D_(XV-1), D_(XV-2t),J_(XV-1), J_(XV-2), and K_(XV-1), is a covalent bond, no more than oneof D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) is O, no morethan one of D_(XV-), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) is S,one of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) must be acovalent bond when two of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), andK_(XV), are O and S, and no more than four of D_(XV-1), D_(XV-2),J_(XV-1), J_(XV-2), and K_(XV), are N;

B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4) J_(XV-3), J_(XV-4), and K_(XV-2)are independently selected from the group consisting of C, C(R_(XV-30)),N, O, S and a covalent bond with the provisos that no more than 5 ofB_(XV-1, B) _(XV-2, D) _(XV-3), J_(XV-4), J_(XV-3, J) _(XV-4), andK_(XV-2) are a covalent bond, no more than two of B_(XV-1, B) _(XV-2, D)_(XV-3, D) _(XV-4), J_(XV-3, J) _(XV-4), and K_(XV-2) are 0, no morethan two of B_(XV-1, B) _(XV-2, D) _(XV-3), D_(XV-4), J_(XV-3),J_(XV-4), and K_(XV-2) are S, no more than two of B_(XV-1), B_(XV-2),D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2) are simultaneouslyO and S, and no more than two of B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4),J_(XV-3), J_(XV-4), and K_(XV-2) are N;

B_(XV-1) and D_(XV-3), D_(XV-3) and J_(XV-3), J_(XV-3) and K_(XV-2)K_(XV-2) and J_(XV-4), J_(XV-4) and D_(XV-4), and D_(XV-4) and B_(XV-2)are independently selected to form an in-ring spacer pair wherein saidspacer pair is selected from the group consisting ofC(R_(XV-33))═C(R_(XV-35)) and N═N with the provisos that AQ-2 must be aring of at least five contiguous members, that no more than two of thegroup of said spacer pairs are simultaneously C(R_(XV-33))═C(R_(XV-35))and that no more than one of the group of said spacer pairs can be N═Nunless the other spacer pairs are other thanC(R_(XV-33))═C(R_(XV-35)),O, N, and S;

R_(XV-1) is selected from the group consisting of haloalkyl andhaloalkoxymethyl;

R_(XV-2) is selected from the group consisting of hydrido, aryl, alkyl,alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl and heteroaryl;

R_(XV-3) is selected from the group consisting of hydrido, aryl, alkyl,alkenyl, haloalkyl, and haloalkoxyalkyl;

Y_(XV) is selected from the group consisting of a covalent single bond,(CH₂)_(q) wherein q is an integer selected from 1 through 2 and(CH₂)_(j)—O—(CH₂)_(k) wherein j and k are integers independentlyselected from 0 through 1;

Z_(XV) is selected from the group consisting of covalent single bond,(CH₂)_(q) wherein q is an integer selected from 1 through 2, and(CH₂)_(j)—O—(CH₂)_(k) wherein j and k are integers independentlyselected from 0 through 1;

R_(XV-4), R_(XV-8), R_(XV-9) and R_(XV-13) are independently selectedfrom the group consisting of hydrido, halo, haloalkyl, and alkyl;

R_(XV-30) is selected from the group consisting of hydrido, alkoxy,alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl,alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso thatR_(XV-30) is selected to maintain the tetravalent nature of carbon,trivalent nature of nitrogen, the divalent nature of sulfur, and thedivalent nature of oxygen;

R_(XV-30), when bonded to A_(XV-I), is taken together to form anintra-ring linear spacer connecting the A_(XV-I)-carbon at the point ofattachment of R_(XV-30) to the point of bonding of a group selected fromthe group consisting of R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-31), andR_(XV-32) wherein said intra-ring linear spacer is selected from thegroup consisting of a covalent single bond and a spacer moiety havingfrom 1 through 6 contiguous atoms to form a ring selected from the groupconsisting of a cycloalkyl having from 3 through 10 contiguous members,a cycloalkenyl having from 5 through 10 contiguous members, and aheterocyclyl having from 5 through 10 contiguous members;

R_(XV-30), when bonded to A_(XV-I), is taken together to form anintra-ring branched spacer connecting the A_(XV-I)-carbon at the pointof attachment of R_(XV-30) to the points of bonding of each member ofany one of substituent pairs selected from the group consisting ofsubsitituent pairs R_(XV-10) and R_(XV-11), R_(XV-10) and R_(XV-31),R_(XV-10) and R_(XV-32), R_(XV-10) and R_(XV-12), R_(XV-11) andR_(XV-31), R_(XV-11) and R_(XV-32), R_(XV-11) and R_(XV-12), R_(XV-31)and R_(XV-32), R_(XV-31) and R_(XV-12) and R_(XV-32) and R_(XV-12) andwherein said intra-ring branched spacer is selected to form two ringsselected from the group consisting of cycloalkyl having from 3 through10 contiguous members, cycloalkenyl having from 5 through 10 contiguousmembers, and heterocyclyl having from 5 through 10 contiguous members;

R_(XV-4), R_(XV-5), R_(XV-6), R_(XV-7), R_(XV-8), R_(XV-9), R_(XV-10),R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), R_(XV-32), R_(XV-33),R_(XV-34), R_(XV-35), and R_(XV-36) are independently selected from thegroup consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy,cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy,aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl,perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl,aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,alkylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the provisos that R_(XV-4), R_(XV-5),R_(XV-6), R_(XV-7), R_(XV-8), R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12),R_(XV-13), R_(XV-31), R_(XV-32), R_(XV-33), R_(XV-34), R_(XV-35), andR_(XV-36) are each independently selected to maintain the tetravalentnature of carbon, trivalent nature of nitrogen, the divalent nature ofsulfur, and the divalent nature of oxygen, that no more than three ofthe R_(XV-33) and R_(XV-34) substituents are simultaneously selectedfrom other than the group consisting of hydrido and halo, and that nomore than three of the R_(XV-35) and R_(XV-36) substituents aresimultaneously selected from other than the group consisting of hydridoand halo;

R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31) andR_(XV-32) are independently selected to be oxo with the provisos thatB_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2)are independently selected from the group consisting of C and S, no morethan two of R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13),R_(XV-31), and R_(XV-32) are simultaneously oxo, and that R_(XV-9),R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), and R_(XV-32) areeach independently selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

R_(XV-4) and R_(XV-5), R_(XV-5) and R_(XV-6), R_(XV-6)and R_(XV-7),R_(XV-7) and R_(XV-8), R_(XV-9) and R_(XV-10), R_(XV-10) and R_(XV-11),R_(XV-11) and R_(XV-31), R_(XV-31) and R_(XV-32), R_(XV-32) andR_(XV-12), and R_(XV-12) and R_(XV-13) are independently selected toform spacer pairs wherein a spacer pair is taken together to form alinear moiety having from 3 through 6 contiguous atoms connecting thepoints of bonding of said spacer pair members to form a ring selectedfrom the group consisting of a cycloalkenyl ring having 5 through 8contiguous members, a partially saturated heterocyclyl ring having 5through 8 contiguous members, a heteroaryl ring having 5 through 6contiguous members, and an aryl with the provisos that no more than oneof the group consisting of spacer pairs R_(XV-4) and R_(XV-5),R_(XV-5 and R) _(XV-6), R_(XV-6) and R_(XV-7), R_(XV-7) and R_(XV-8) isused at the same time and that no more than one of the group consistingof spacer pairs R_(XV-9) and R_(XV-10), R_(XV-10) and R_(XV-11),R_(XV-11) and R_(XV-31), R_(XV-31) and R_(XV-32), R_(XV-32) andR_(XV-12) and R_(XV-12) and R_(XV-13) are used at the same time;

R_(XV-9) and R_(XV-11), R_(XV-9) and R_(XV-12), R_(XV-9) and R_(XV-13)R_(XV-9) and R_(XV-31), R_(XV-9) and R_(XV-32), R_(XV-10) and R_(XV-12),R_(XV-10) and R_(XV-13), R_(XV-10) and R_(XV-31), R_(XV-10) andR_(XV-32), R_(XV-11) and R_(XV-12), R_(XV-11) and R_(XV-13), R_(XV-11)and R_(XV-32), R_(XV-12) and R_(XV-31), R_(XV-13) and R_(XV-31), andR_(XV-13) and R_(XV-32) are independently selected to form a spacer pairwherein said spacer pair is taken together to form a linear spacermoiety selected from the group consisting of a covalent single bond anda moiety having from 1 through 3 contiguous atoms to form a ringselected from the group consisting of a cycloalkyl having from 3 through8 contiguous members, a cycloalkenyl having from 5 through 8 contiguousmembers, a saturated heterocyclyl having from 5 through 8 contiguousmembers and a partially saturated heterocyclyl having from 5 through 8contiguous members with the provisos that no more than one of said groupof spacer pairs is used at the same time;

R_(XV-37) and R_(XV-38) are independently selected from the groupconsisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo,haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl,haloalkoxy, and haloalkoxyalkyl.

Compounds of Formula XV are disclosed in WO 00/18723, the entiredisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XV:

-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexylmethyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl]](3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl](cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol:-   3-[[3-(3-isopropylphenoxy)phenyl](cyclopentylmethyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,11-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopropylmethy)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phennyl](cyclopropylmethyl)amino]-1,1,1-triflouro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy]phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclopropylmethyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy]phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)-cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl]phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-cyclohexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl]phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifloromethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-isopropoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl](3-cyclopentyloxycyclohexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl]phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-pentafluoroethylcyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-propyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-difluropropyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]]3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;    and-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(phenoxy)propyl]amino]-1,1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of (R)-chiral halogenated 1-substitutedamino-(n+1)-alkanols having the Formula XVI

and pharmaceutically acceptable forms thereof, wherein:

n_(XVI), is an integer selected from 1 through 4;

X_(XVI) is oxy;

R_(XVI-1) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the provisothat R_(XVI-1) has a higher Cahn-lngold-Prelog stereochemical systemranking than both R_(XVI-2) and (CHR_(XVI-3))_(n)—N(A_(XVI-))Q_(XVI)wherein A_(XVI) is Formula XVI-(II) and Q is Formula XVI-(II);

R_(XVI-16) is selected from the group consisting of hydrido, alkyl,acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selected from thegroup consisting of a covalent single bond and a linear spacer moietyhaving a chain length of 1 to 4 atoms linked to the point of bonding ofany aromatic substituent selected from the group consisting ofR_(XVI-4), R_(XVI-8), R_(XVI-9), and R_(XVI-13) to form a heterocyclylring having from 5 through 10 contiguous members;

D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) areindependently selected from the group consisting of C, N, O, S andcovalent bond with the provisos that no more than one of D_(XVI-1),D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) is a covalent bond, nomore than one D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1)is be O, no more than one of D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2)and K_(XVI-1) is S, one of D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2)and K_(XVI-1), must be a covalent bond when two of D_(XVI-1), D_(XVI-2),J_(XVI-1), J_(XVI-2) and K_(XVI-1) are O and S, and no more than four ofD_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) is N;

D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) areindependently selected from the group consisting of C, N, O, S andcovalent bond with the provisos that no more than one is a covalentbond, no more than one of D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) andK_(XVI-2) is 0, no more than one of D_(XVI-3), D_(XVI-49) J_(XVI-3),J_(XVI-4) and K_(XVI-2) is S, no more than two of D_(XVI-3), D_(XVI-4),J_(XVI-3), J_(XVI-4) and K_(XVI-2) is O and S, one of D_(XVI-3),D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) must be a covalent bondwhen two of D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) areO and S, and no more than four of D_(XVI-3), D_(XVI-4), J_(XVI-3),J_(XVI-4) and K_(XVI-2) are N;

R_(XVI-2) is selected from the group consisting of hydrido, aryl,aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl,halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, andcarboalkoxycyanoalkyl, with the proviso that R_(XVI-2) has a lowerCahn-Ingold-Prelog system ranking than both R_(XVI-1) and(CHR_(XVI-3))_(n)—N(A_(XVI))Q_(XVI);

R_(XVI-3) is selected from the group consisting of hydrido, hydroxy,cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl,heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl,carboxamide, and carboxamidoalkyl, with the provisos that(CHR_(XVI-3))_(n)—N(A_(XVI))Q_(XVI) has a lower Cahn-lngold-Prelogstereochemical system ranking than R_(XVI-1) and a higherCahn-lngold-Prelog stereochemical system ranking than R_(XVI-2);

Y_(XVI) is selected from a group consisting of a covalent single bond,(C(R_(XVI-14))₂)_(q) wherein q is an integer selected from 1 and 2 and(CH(R_(XVI-14)))_(g)—W_(XVI)—(CH(R_(XVI-14)))_(p) wherein g and p areintegers independently selected from 0 and 1;

R_(XVI-14) is selected from the group consisting of hydrido, hydroxy,cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

Z_(XVI) is selected from a group consisting of a covalent single bond,(C(R_(XVI -15))₂)_(q), wherein q is an integer selected from 1 and 2,and (CH(R_(XVI-15)))_(j)—W_(XVI)-(CH(R_(XVI-)15))_(k) wherein j and kare integers independently selected from 0 and 1;

W_(XVI) is selected from the group consisting of O, C(O),C(S),C(O)N(R_(XVI-14)), C(S)N(R_(XVI-14)),(R_(XVI-14))NC(O),(R_(XVI-14))NC(S), S, S(O), S(O)₂, S(O)₂N(R_(XVI-14)),(R_(XVI-14))NS(O)₂, and N(R_(XVI-14)) with the proviso that R_(XVI-14)is other than cyano;

R_(XVI-5) is selected, from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

R_(XVI-4), R_(XVI-5), R_(XVI-6), R_(XVI-7), R_(XVI-8), R_(XVI-9),R_(XVI-10), R_(XVI-11), R_(XVI-12), and R_(XVI-13) are independentlyselected, from the group consisting of hydrido, carboxy,heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamino, heteroaralkyl,heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl,cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio,nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl, amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl,alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl,heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturatedheterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that R_(XVI-4), R_(XVI-5),R_(XVI-6), R_(XVI-7), R_(XVI-8), R_(XVI-9), R_(XVI-10), R_(XVI-11),R_(XVI-12), and R_(XVI-13) are each independently selected to maintainthe tetravalent nature of carbon, trivalent nature of nitrogen, thedivalent nature of sulfur, and the divalent nature of oxygen;

R_(XVI-4) and R_(XVI-5), R_(XVI-5) and R_(XVI-6), R_(XVI-6) andR_(XVI -7), R_(XVI-7) and R_(XVI-9), R_(XVI-9) and R_(XVI-10),R_(XVI-10) and R_(XVI-11), R_(XVI-11) and R_(XVI-12) and R_(XVI-12) andR_(XIV-13) are independently selected to form spacer pairs wherein aspacer pair is taken together to form a linear moiety having from 3through 6 contiguous atoms connecting the points of bonding of saidspacer pair members to form a ring selected from the group consisting ofa cycloalkenyl ring having 5 through 8 contiguous members, a partiallysaturated heterocyclyl ring having 5 through 8 contiguous members, aheteroaryl ring having 5 through 6 contiguous members, and an aryl withthe provisos that no more than one of the group consisting of spacerpairs R_(XVI-4) and R_(XVI-5), R_(XVI-5) and R_(XVI-6), R_(XVI-6) andR_(XVI-7), and R_(XVI-7) and R_(XVI-8) is used at the same time and thatno more than one of the group consisting of spacer pairs R_(XIV-9) andR_(XVI-10), R_(XVI-10) and R_(XVI-11), R_(XVI-11) and R_(XVI-12), andR_(XVI-12) and R_(XV-113) can be used at the same time;

R_(XVI-4) and R_(XVI-9), R_(XVI-4) and R_(XVI-13), R_(XVI-8) andR_(XVI-9), and R_(XVI-8) and R_(XVI-13) is independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear moiety wherein said linear moiety forms a ring selected from thegroup consisting of a partially saturated heterocyclyl ring having from5 through 8 contiguous members and a heteroaryl ring having from 5through 6 contiguous members with the proviso that no more than one ofthe group consisting of spacer pairs R_(XVI-4) and R_(XVI-9), R_(XVI-4)and R_(XVI-13), P_(XVI-8) and R_(XVI-9), and R_(XVI-8) and R_(XVI-13) isused at the same time.

Compounds of Formula XVI are disclosed in WO 00/18724, the entiredisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XVI:

-   (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol:-   (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2,-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]-   methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoro-methyl)phenyl]-   methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]-   methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(3-trifuoromethylthio)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(pentafluoroethyl)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)    phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(pentafluoroethyl)    phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(pentafluoroethyl)    phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(phenoxy)phenyl][[3(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,11-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(pentafluoroethyl)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-trifluoromethbxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)    phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)    phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol;-   (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(heptafluoropropyl)    phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)    phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)    phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)    phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-4trifluoro-2-propanol;-   (2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-3-propanol;-   (2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(N,N-dimethylamino,phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]-   methoxy]phenyl]amino]-1,1,1-trifluoro-3-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]-   methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]-   methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-flouro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,    1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro    -4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro    -2-propanol;-   (3R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]-   methyl]amino]-1,1,1-trifluoro-2-propanol; and-   (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of quinolines of Formula XVII

and pharmaceutically acceptable forms thereof, wherein:

A_(XVII) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with up to five identical or differentsubstituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy or a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in theform of a group according to the formula —NR_(XVII-4)R_(XVII-5), wherein

R_(XVII-4) and R_(XVII-5) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms,

D_(XVII) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with a phenyl, nitro, halogen, trifluoromethyl ortrifluoromethoxy, or a radical according to the formulaR_(XVII-6)—L_(XVII)—,

or R_(XVII-10)—T_(XVII)—V_(XVII)—X_(XVII)—

wherein

R_(XVII-6), R_(XVII-7), R_(XVII-10) denote, independently from oneanother, a cycloalkyl containing 3 to 6 carbon atoms, or an arylcontaining 6 to 10 carbon atom or a 5- to 7-membered, optionallybenzo-condensed, saturated or unsaturated, mono-, bi- or tricyclicheterocycle containing up to 4 heteroatoms from the series of S, Nand/or O, wherein the rings are optionally substituted, in the case ofthe nitrogen-containing rings also via the N function, with up to fiveidentical or different substituents in the form of a halogen,trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, astraight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl containing up to 6 carbon atoms each, an aryl ortrifluoromethyl-substituted aryl containing 6 to 10 carbon atoms each,or an optionally benzo-condensed, aromatic 5to 7-membered heterocyclecontaining up to 3 heteoatoms from the series of S, N and/or O, and/orin the form of a group according to the formula —OR_(XVII-11),—SR_(XVII-12), —SO₂R_(XVII-13), or —NR_(XVII-14)R_(XVII-15);

R_(XVII-11), R_(XVII-12), and R_(XVII-13) denote, independently from oneanother, an aryl containing 6 to 10 carbon atoms, which is in turnsubstituted with up to two identical or different substituents in theform of a phenyl, halogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms,

R_(XVII-14) and R_(XVII-15) are identical or different and have themeaning of R_(XVII-4) and R_(XVII-5) given above, or

R_(XVII-6) and/or R_(XVII-7) denote a radical according to the formula

R_(XVII-8) denotes a hydrogen or halogen, and

R_(XVII-9) denotes a hydrogen, halogen, azido, trifluoromethyl,hydroxyl, trifluoromethoxy, a straight-chain or branched alkoxy or alkylcontaining up to 6 carbon atoms each, or a radical according to theformula NR_(XVII-16)R_(XVII-17;)

R_(XVII-16) and R_(XV-17) are identical or different and have themeaning of R_(XVI-4) and R_(XVII-5) above; or

R_(XVII-8) and R_(XVII-9) together form a radical according to theformula ═O or ═NR_(XVII-18);

R_(XVII-18) denotes a hydrogen or a straight-chain or branched alkyl,alkoxy or acyl containing up to 6 carbon atoms each;

L_(XVII) denotes a straight-chain or branched alkylene or alkenylenechain containing up to 8 carbon atoms each, which are optionallysubstituted with up to two hydroxyl groups;

T_(XVII) and X_(XVII) are identical or different and denote astraight-chain or branched alkylene chain containing up to 8 carbonatoms; or

T_(XVII) and X_(XVII) denotes a bond;

V_(XVII) denotes an oxygen or sulfur atom or —NR_(XVII-19);

R_(XVII-19) denotes a hydrogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms or a phenyl;

E_(XVII) denotes a cycloalkyl containing 3 to 8 carbon atoms, or astraight-chain or branched alkyl containing up to 8 carbon atoms, whichis optionally substituted with a cycloalkyl containing 3 to 8 carbonatoms or a hydroxyl, or a phenyl, which is optionally substituted with ahalogen or trifluoromethyl;

R_(XVII-1) and R_(XVII-2) are identical or different and denote acycloalkyl containing 3 to 8 carbon atoms, hydrogen, nitro, halogen,trifluoromethyl, trifluoromethoxy, carboxy, hydroxy, cyano, astraight-chain or branched acyl, alkoxycarbonyl or alkoxy with up to 6carbon atoms, or NR_(XVII-20)R_(XVII-21);

R_(XVII-20) and R_(XVII-21) are identical or different and denotehydrogen, phenyl, or a straight-chain or branched alkyl with up to 6carbon atoms; and or

R_(XVII-1) and/or R_(XVII-2) are straight-chain or branched alkyl withup to 6 carbon atoms, optionally substituted with halogen,trifluoromethoxy, hydroxy, or a straight-chain or branched alkoxy withup to 4 carbon atoms, aryl containing 6-10 carbon atoms optionallysubstituted with up to five of the same or different substituentsselected from halogen, cyano, hydroxy, trifluoromethyl,trifluoromethoxy, nitro, straight-chain or branched alkyl, acyl,hydroxyalkyl, alkoxy with up to 7 carbon atoms andNR_(XVII-22)R_(XVII-23);

R_(XVII-22) and R_(XVII-23) are identical or different and denotehydrogen, phenyl or a straight-chain or branched akyl up to 6 carbonatoms; and/or R_(XVII-1) and R_(XVII-2) taken together form astraight-chain or branched alkene or alkane with up to 6 carbon atomsoptionally substituted with halogen, trifluoromethyl, hydroxy orstraight-chain or branched alkoxy with up to 5 carbon atoms;

R_(XVII-3) denotes hydrogen, a straight-chain or branched acyl with upto 20 carbon atoms, a benzoyl optionally substituted with halogen,trifluoromethyl, nitro or trifluoromethoxy, a straight-chained orbranched fluoroacyl with up to 8 carbon atoms and 7 fluoro atoms, acycloalkyl with 3 to 7 carbon atoms, a straight chained or branchedalkyl with up to 8 carbon atoms optionally substituted with hydroxyl, astraight-chained or branched alkoxy with up to 6 carbon atoms optionallysubstituted with phenyl which may in turn be substituted with halogen,nitro, trifluoromethyl, trifluoromethoxy, or phenyl or a tetrazolsubstitued phenyl, and/or an alkyl that is optionally substituted with agroup according to the formula —OR_(XVII-24);

R_(XVII-24) is a straight-chained or branched acyl with up to 4 carbonatoms or benzyl.

Compounds of Formula XVII are disclosed in WO 98/39299, the entiredisclosure is incorporated by reference.

Another class of CETP inhibitors that finds utility with the presentinvention consists of 4-Phenyltetrahydroquinolines of Formula XVIII

N oxides thereof, and pharmaceutically acceptable forms thereof,wherein:

A_(XVII) denotes a phenyl optionally substituted with up to twoidentical or different substituents in the form of halogen,trifluoromethyl or a straight-chain or branched alkyl or alkoxycontaining up to three carbon atoms;

D_(XVII) denotes the formula

or R_(XVIII-8)—CH₂—O—CH₂—;

R_(XVII-5) and R_(XVII-6) are taken together to form ═O; or

R_(XVII-5) denotes hydrogen and R_(XVII-6) denotes halogen or hydrogen;or

R_(XVIII-5) and R_(XVII-6) denote hydrogen;

R_(XVII-7) and R_(XVII-8) are identical or different and denote phenyl,naphthyl, benzothiazolyl, quinolinyl, pyrimidyl or pyridyl with up tofour identical or different substituents in the form of halogen,trifluoromethyl, nitro, cyano, trifluoromethoxy, —SO₂—CH₃ orNR_(XVII-9)R_(XVII-10);

R_(XVII-9) and R_(XVII-10) are identical or different and denotehydrogen or a straight-chained or branched alkyl of up to three carbonatoms;

E_(XVII) denotes a cycloalkyl of from three to six carbon atoms or astraight-chained or branched alkyl of up to eight carbon atoms;

R_(XVII-1) denotes hydroxy;

R_(XVII-2) denotes hydrogen or methyl;

R_(XVII-3) and R_(XVII-4) are identical or different and denotestraight-chained or branched alkyl of up to three carbon atoms; or

R_(XVII-3) and R_(XVII-4) taken together form an alkenylene made up ofbetween two and four carbon atoms.

Compounds of Formula XVIII are disclosed in WO 99/15504, the entiredisclosure of which is incorporated by reference.

Another class of CETP inhibitors that finds utility with the presentinvention consists of aminoethanol derivatives of Formula XIX

and pharmaceutically acceptable forms thereof, wherein:

-   Ar_(XIX-1) denotes an aromatic ring group that may contain a    substituting group;-   Ar_(XIX-2) denotes an aromatic ring group that may contain a    substituting group;-   R_(XIX) denotes an acyl group;-   R′_(XIX) denotes a hydrogen atom or hydrocarbon group that may    contain a substituting group; and-   OR″_(XIX) denotes a hydroxyl group that may be protected.

Compounds of Formula XIX are disclosed in WO 2002/059077, the entiredisclosure of which is incorporated by reference.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XIX or their salts:

-   N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cyclopentene-1-carboxamide,-   4-fluoro-N-((1R,2S)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalene    carboxamide;-   N-[(1R,2S)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cyclopentene-1-carboxamide;-   N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-5,6-dihydronaphthalene-1-carboxamide;-   N-[(1    RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene    -1-carboxamide;-   4-fluoro-N-[(1R,2S)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]naphthalene-1-carboxamide;-   N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-5,6,7,8-tetrahydrobenzo[a]cyclooctene-1-carboxamide;-   N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-(4-isopropylbenzyl)ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide;-   N-((1RS,2SR)-2-(3-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide;-   N-((1RS,2SR)-2-hydroxy-2-(4-phenoxyphenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide;-   N-[(1RS,2SR)-2-(4-chlorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide;-   N-((1RS,2SR)-2-hydroxy-2-(4-phenyloxy)phenyl)-1-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cyclohepte    ne -1-carboxamide;-   N-((1RS,2SR)-2-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)    -2-hydroxy-1-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide;-   N-((1RS,2SR)-2-(2-fluoropyridine-4-yl)-2-hydroxy-1-((3-((1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene    -1-carboxamide;-   N-((1RS,2RS)-2-(6-fluoropyridine-2-yl)-2-hydroxy-1-((3-((1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide;-   N-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(3-chlorophenyl)    -2-hydroxyethyl]-5-chloro-1-napthoamide;-   4-fluoro-N-{(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy1-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]ethyl}-1-naphthoamide.

In a preferred embodiment, the CETP inhibitor is[2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester also known as torcetrapib.Torcetrapib is shown by the following Formula

CETP inhibitors, in particular torcetrapib, and methods for preparingsuch compounds are disclosed in detail in U.S. Pat. Nos. 6,197,786 and6,313,142, in PCT Application Nos. WO 01/40190A1, WO 02/088085A2, and WO02/088069A2, the disclosures of which are herein incorporated byreference. Torcetrapib has an unusually low solubility in aqueousenvironments such as the lumenal fluid of the human GI tract. Theaqueous solubility of torceptrapib is less than about 0.04 μg/ml.Torcetrapib must be presented to the GI tract in a solubility-enhancedform in order to achieve a sufficient drug concentration in the GI tractin order to achieve sufficient absorption into the blood to elicit thedesired therapeutic effect.

Solid Amorphous Dispersions of CETP Inhibitors

The CETP inhibitor and concentration-enhancing polymer are combined andformed into a solid amorphous dispersion. By solid amorphous dispersionis meant a solid material in which at least a portion of the CETPinhibitor is in the amorphous form and dispersed in the polymer.Preferably, at least a major portion of the CETP inhibitor in the solidamorphous dispersion is amorphous. By “amorphous” is meant simply thatthe CETP inhibitor is in a non-crystalline state. As used herein, theterm “a major portion” of the CETP inhibitor means that at least 60 wt %of the drug in the solid amorphous dispersion is in the amorphous form,rather than the crystalline form. Preferably, the CETP inhibitor in thesolid amorphous dispersion is substantially amorphous. As used herein,“substantially amorphous” means that the amount of the CETP inhibitor incrystalline form does not exceed about 25 wt %. More preferably, theCETP inhibitor in the solid amorphous dispersion is “almost completelyamorphous,” meaning that the amount of CETP inhibitor in the crystallineform does not exceed about 10 wt %. Amounts of crystalline CETPinhibitor may be measured by Powder X-Ray Diffraction (PXRD), ScanningElectron Microscope (SEM) analysis, differential scanning calorimetry(DSC), or any other standard quantitative measurement.

The solid dispersions may contain from about 1 to about 80 wt % CETPinhibitor, depending on the dose of the CETP inhibitor and theeffectiveness of the concentration-enhancing polymer. Enhancement ofaqueous CETP inhibitor concentrations and relative bioavailability aretypically best at low CETP inhibitor levels, typically less than about25 to about 40 wt %. However, due to the practical limit of the dosageform size, higher CETP inhibitor levels may be preferred and in manycases perform well.

The amorphous CETP inhibitor can exist within the solid amorphousdispersion in relatively pure amorphous drug domains or regions, as asolid solution of drug homogeneously distributed throughout the polymeror any combination of these states or those states that lie intermediatebetween them. The solid amorphous dispersion is preferably substantiallyhomogeneous so that the amorphous CETP inhibitor is dispersed ashomogeneously as possible throughout the polymer. As used herein,“substantially homogeneous” means that the fraction of CETP inhibitorthat is present in relatively pure amorphous drug domains or regionswithin the solid amorphous dispersion is relatively small, on the orderof less than 20 wt %, and preferably less than 10 wt % of the totalamount of drug. Solid amorphous dispersions that are substantiallyhomogeneous generally are more physically stable and have improvedconcentration-enhancing properties and, in turn, improvedbioavailability, relative to nonhomogeneous dispersions.

In cases where the CETP inhibitor and the polymer have glass transitiontemperatures sufficiently far apart (greater than about 20° C.), thefraction of drug that is present in relatively pure amorphous drugdomains or regions within the solid amorphous dispersion can bedetermined by examining the glass transition temperature (T_(g)) of thesolid amorphous dispersion. T_(g) as used herein is the characteristictemperature where a glassy material, upon gradual heating, undergoes arelatively rapid (e.g., in 10 to 100 seconds) physical change from aglassy state to a rubbery state. The T_(g) of an amorphous material suchas a polymer, drug, or dispersion can be measured by several techniques,including by a dynamic mechanical analyzer (DMA), a dilatometer, adielectric analyzer, and by DSC. The exact values measured by eachtechnique can vary somewhat, but usually fall within 10 to 30° C. ofeach other. When the solid amorphous dispersion exhibits a single T_(g),the amount of CETP inhibitor in pure amorphous drug domains or regionsin the solid amorphous dispersion is generally has less than about 10 wt%, confirming that the solid amorphous dispersion is substantiallyhomogeneous. This is in contrast to a simple physical mixture of pureamorphous drug particles and pure amorphous polymer particles whichgenerally display two distinct T_(g)s, one being that of the drug andone that of the polymer. For a solid amorphous dispersion that exhibitstwo distinct T_(g)s, one in the proximity of the drug T_(g) and one ofthe remaining drug/polymer dispersion, at least a portion of the drug ispresent in relatively pure amorphous domains. The amount of CETPinhibitor present in relatively pure amorphous drug domains or regionsmay be determined by first preparing calibration standards ofsubstantially homogeneous dispersions to determine T_(g) of the solidamorphous dispersion versus drug loading in the dispersion. From thesecalibration data and the T_(g) of the drug/polymer dispersion, thefraction of CETP inhibitor in relatively pure amorphous drug domains orregions can be determined. Alternatively, the amount of CETP inhibitorpresent in relatively pure amorphous drug domains or regions may bedetermined by comparing the magnitude of the heat capacity for thetransition in the proximity of the drug T_(g) with calibration standardsconsisting essentially of a physical mixture of amorphous drug andpolymer. In either case, a solid amorphous dispersion is considered tobe substantially homogeneous if the fraction of CETP inhibitor that ispresent in relatively pure amorphous drug domains or regions within thesolid amorphous dispersion is less than 20 wt %, and preferably lessthan 10 wt % of the total amount of CETP inhibitor.

Acidic Concentration-Enhancing Polymers

The solid amorphous dispersions of the present invention comprise a CETPinhibitor and an acidic concentration-enhancing polymer. The acidicconcentration-enhancing polymers suitable for use in the solid amorphousdispersions should be inert, in the sense that they do not chemicallyreact with the CETP inhibitor in an adverse manner. The polymer shouldhave an aqueous solubility of at least 0.1 mg/mL over at least a portionof the pH range of 1-8.

By “acidic polymer” is meant any polymer that possesses a significantnumber of acidic moieties. In general, a significant number of acidicmoieties would be greater than or equal to about 0.1 milliequivalents ofacidic moieties per gram of polymer. “Acidic moieties” include anyfunctional groups that are sufficiently acidic that, in contact with ordissolved in water, can at least partially donate a hydrogen cation towater and thus increase the hydrogen-ion concentration. This definitionincludes any functional group or “substituent,” as it is termed when thefunctional group is covalently attached to a polymer, that has a pK_(a)of less than about 10. Here, the term pK_(a) is used in its traditionalform, the pK_(a) being the negative logarithm of the acid ionizationconstant. The pK_(a) will be influenced by such factors as solvent,temperature, water content, and ionic strength of the media or matrix inwhich the acid resides. Unless otherwise noted, the pK_(a) is assumed tobe measured in distilled water at 25° C. Since in general, the moreacidic the polymer the more useful the invention, the invention ispreferred for polymers with functional groups with pK_(a)s of less thanabout 7, and even more preferred with pK_(a)s of less than about 6.Exemplary classes of functional groups that are included in the abovedescription include carboxylic acids, thiocarboxylic acids, phosphates,phenolic groups, and sulfonates. Such functional groups may make up theprimary structure of the polymer such as for polyacrylic acid, but moregenerally are covalently attached to the backbone of the parent polymerand thus are termed “substituents.”

It is preferred that the concentration-enhancing polymer be“amphiphilic” in nature, meaning that the polymer has hydrophobic andhydrophilic portions. Amphiphilic polymers are preferred because it isbelieved that such polymers tend to have relatively strong interactionswith the drug and may promote the formation of various types ofpolymer/drug assemblies in solution. A particularly preferred class ofamphiphilic polymers are those that are ionizable, the ionizableportions of such polymers, when ionized, constituting at least a portionof the hydrophilic portions of the polymer. For example, while notwishing to be bound by a particular theory, such polymer/drug assembliesmay comprise hydrophobic drug clusters surrounded by theconcentration-enhancing polymer with the polymer's hydrophobic regionsturned inward towards the drug and the hydrophilic regions of thepolymer turned outward toward the aqueous environment. Alternatively,depending on the specific chemical nature of the drug, the ionizedfunctional groups of the polymer may associate, for example, viaion-pairing or hydrogen bonds, with ionic or polar groups of the drug.In the case of ionizable polymers, the hydrophilic regions of thepolymer would include the ionized functional groups. In addition, therepulsion of the like charges of the ionized groups of such polymers(where the polymer is ionizable) may serve to limit the size of thepolymer/drug assemblies to the nanometer or submicron scale. Suchdrug/concentration-enhancing polymer assemblies in solution may wellresemble charged polymeric micellar-like structures. In any case,regardless of the mechanism of action, the inventors have observed thatsuch amphiphilic polymers, particularly ionizable cellulosic polymerssuch as those listed below, have been shown to interact with drug so asto maintain a higher concentration of drug in an aqueous useenvironment.

One class of acidic concentration-enhancing polymers suitable for usewith the present invention comprises ionizable non-cellulosic polymers.Exemplary polymers include: carboxylic acid-functionalized vinylpolymers, such as the carboxylic acid functionalized polymethacrylatesand carboxylic acid functionalized polyacrylates such as the EUDRAGIT®series manufactured by Rohm Tech Inc., of Maiden, Mass.; proteins suchas gelatin and albumin; and carboxylic acid functionalized starches suchas starch glycolate.

Non-cellulosic polymers that are amphiphilic are copolymers of arelatively hydrophilic and a relatively hydrophobic monomer. Examplesinclude acrylate and methacrylate copolymers. Exemplary commercialgrades of such copolymers include the EUDRAGIT® series, which arecopolymers of methacrylates and acrylates.

A preferred class of polymers comprises acidic ionizable cellulosicpolymers with at least one ester- and/or ether-linked substituent inwhich the polymer has a degree of substitution of at least 0.05 for eachsubstituent. It should be noted that in the polymer nomenclature usedherein, ether-linked substituents are recited prior to “cellulose” asthe moiety attached to the ether group; for example, “ethylbenzoic acidcellulose” has ethoxybenzoic acid substituents. Analogously,ester-linked substituents are recited after “cellulose” as thecarboxylate; for example, “cellulose phthalate” has one carboxylic acidof each phthalate moiety ester-linked to the polymer and the othercarboxylic acid unreacted.

It should also be noted that a polymer name such as “cellulose acetatephthalate” (CAP) refers to any of the family of cellulosic polymers thathave acetate and phthalate groups attached via ester linkages to asignificant fraction of the cellulosic polymer's hydroxyl groups.Generally, the degree of substitution of each substituent group canrange from 0.05 to 2.9 as long as the other criteria of the polymer aremet. “Degree of substitution” refers to the average number of the threehydroxyls per saccharide repeat unit on the cellulose chain that havebeen substituted. For example, if all of the hydroxyls on the cellulosechain have been phthalate-substituted, the phthalate degree ofsubstitution is 3. Also included within each polymer family type arecellulosic polymers that have additional substituents added inrelatively small amounts that do not substantially alter the performanceof the polymer.

Amphiphilic cellulosics comprise polymers in which the parent cellulosicpolymer has both hydrophilic and hydrophobic substituents. Hydrophobicsubstituents may be essentially any substituent that, if substituted toa high enough level or degree of substitution, can render the cellulosicpolymer essentially aqueous-insoluble. Examples of hydrophobicsubstituents include ether-linked alkyl groups such as methyl, ethyl,propyl, butyl, etc.; or ester-linked alkyl groups such as acetate,propionate, butyrate, etc.; and ether- and/or ester-linked aryl groupssuch as phenyl, benzoate, or phenylate. Hydrophilic regions of thepolymer can be either those portions that are relatively unsubstituted,since the unsubstituted hydroxyls are themselves relatively hydrophilic,or those regions that are substituted with hydrophilic substituents.Hydrophilic substituents include ether- or ester-linked nonionizablegroups such as the hydroxy alkyl substituents hydroxyethyl,hydroxypropyl, and the alkyl ether groups such as ethoxyethoxy ormethoxyethoxy. Particularly preferred hydrophilic substituents are thosethat are ether- or ester-linked ionizable groups such as carboxylicacids, thiocarboxylic acids, substituted phenoxy groups, amines,phosphates or sulfonates.

A preferred class of acidic cellulosic polymers comprises polymers thatare at least partially ionizable at physiologically relevant pH andinclude at least one ionizable substituent, which may be eitherether-linked or ester-linked. Exemplary ether-linked ionizablesubstituents include: carboxylic acids, such as acetic acid, propionicacid, benzoic acid, salicylic acid, alkoxybenzoic acids such asethoxybenzoic acid or propoxybenzoic acid, the various isomers ofalkoxyphthalic acid such as ethoxyphthalic acid and ethoxyisophthalicacid, the various isomers of alkoxynicotinic acid such asethoxynicotinic acid, and the various isomers of picolinic acid such asethoxypicolinic acid, etc.; thiocarboxylic acids, such as thioaceticacid; substituted phenoxy groups, such as hydroxyphenoxy, etc.;phosphates, such as phosphate ethoxy; and sulfonates, such as sulphonateethoxy. Exemplary ester-linked ionizable substituents include:carboxylic acids, such as succinate, citrate, phthalate, terephthalate,isophthalate, trimellitate, and the various isomers ofpyridinedicarboxylic acid, etc.; thiocarboxylic acids, such asthiosuccinate; substituted phenoxy groups, such as amino salicylic acid;phosphates, such as acetyl phosphate; and sulfonates, such as acetylsulfonate. For aromatic-substituted polymers to also have the requisiteaqueous solubility, it is also desirable that sufficient hydrophilicgroups such as hydroxypropyl or carboxylic acid functional groups beattached to the polymer to render the polymer aqueous soluble at leastat pH values where any ionizable groups are ionized. In some cases, thearomatic substituent may itself be ionizable, such as phthalate ortrimellitate substituents.

The polymer may also contain neutral, or non-ionizable substituents,which may be either ether-linked or ester-linked. Exemplary ether-linkednon-ionizable substituents include: alkyl groups, such as methyl, ethyl,propyl, butyl, etc.; hydroxy alkyl groups such as hydroxymethyl,hydroxyethyl, hydroxypropyl, etc.; and aryl groups such as phenyl.Exemplary ester-linked non-ionizable substituents include: alkyl groups,such as acetate, propionate, butyrate, etc.; and aryl groups such asphenylate. However, when aryl groups are included, the polymer may needto include a sufficient amount of a hydrophilic substituent so that thepolymer has at least some water solubility at any physiologicallyrelevant pH of from 1 to 8.

Exemplary cellulosic polymers that are at least partially ionized atphysiologically relevant pHs include: hydroxypropyl methyl celluloseacetate succinate, hydroxypropyl methyl cellulose succinate,hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulosesuccinate, hydroxyethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxyethyl methyl cellulose acetatesuccinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethylcellulose, carboxymethyl cellulose, ethyl carboxymethyl cellulose,carboxymethyl ethyl cellulose, cellulose acetate phthalate, methylcellulose acetate phthalate, ethyl cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalatesuccinate, hydroxypropyl methyl cellulose acetate succinate phthalate,hydroxypropyl methyl cellulose succinate phthalate, cellulose propionatephthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, and ethylpicolinic acid cellulose acetate.

Exemplary acidic cellulosic polymers that meet the definition ofamphiphilic, having hydrophilic and hydrophobic regions include polymerssuch as cellulose acetate phthalate and cellulose acetate trimellitatewhere the cellulosic repeat units that have one or more acetatesubstituents are hydrophobic relative to those that have no acetatesubstituents or have one or more ionized phthalate or trimellitatesubstituents.

A particularly desirable subset of cellulosic acidic polymers are thosethat possess both a carboxylic acid functional aromatic substituent andan alkylate substituent and thus are amphiphilic. Exemplary polymersinclude cellulose acetate phthalate, methyl cellulose acetate phthalate,ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetatephthalate, hydroxylpropyl methyl cellulose phthalate, hydroxypropylmethyl cellulose acetate phthalate, hydroxypropyl cellulose acetatephthalate succinate, cellulose propionate phthalate, hydroxypropylcellulose butyrate phthalate, cellulose acetate trimellitate, methylcellulose acetate trimellitate, ethyl cellulose acetate trimellitate,hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl cellulose acetatetrimellitate succinate, cellulose propionate trimellitate, cellulosebutyrate trimellitate, cellulose acetate terephthalate, celluloseacetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylicacid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate,ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acidcellulose acetate, ethyl phthalic acid cellulose acetate, ethylnicotinic acid cellulose acetate, and ethyl picolinic acid celluloseacetate.

Another particularly desirable subset of amphiphilic cellulosic acidicpolymers are those that possess a non-aromatic carboxylate substituent.Exemplary polymers include hydroxypropyl methyl cellulose acetatesuccinate, hydroxypropyl methyl cellulose succinate, hydroxypropylcellulose acetate succinate, hydroxyethyl methyl cellulose acetatesuccinate, hydroxyethyl methyl cellulose succinate, hydroxyethylcellulose acetate succinate and carboxymethyl ethyl cellulose.

Of these cellulosic polymers that are at least partially ionized atphysiologically relevant pHs, the inventors have found the following tobe most preferred: hydroxypropyl methyl cellulose acetate succinate,hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate,cellulose acetate trimellitate and carboxymethyl ethyl cellulose. Themost preferred is hydroxypropyl methyl cellulose acetate succinate(HPMCAS).

While specific polymers have been discussed as being suitable for use inthe dosage forms of the present invention, blends of such polymers mayalso be suitable. Thus, the term “concentration-enhancing polymer” isintended to include blends of polymers in addition to a single speciesof polymer.

The amount of concentration-enhancing polymer relative to the amount ofCETP inhibitor present in the solid drug dispersions depends on the drugand concentration-enhancing polymer and may vary widely from adrug-to-polymer weight ratio of 0.01 to 5, or from about 1 to about 80wt % drug. However, in most cases, except when the CETP inhibitor doseis quite low, e.g., 25 mg or less, it is preferred that thedrug-to-polymer ratio is greater than 0.05 and less than 2.5 (from about5 to about 70 wt % drug) and often the enhancement in drug concentrationor relative bioavailability is observed at drug-to-polymer ratios of 1(about 50 wt % drug) or less or for some drugs even 0.2 (about 17 wt %drug) or less. In cases where the drug dose is about 25 mg or less, thedrug-to-polymer weight ratio may be significantly less than 0.05. Ingeneral, regardless of the dose, enhancements in drug concentration orrelative bioavailability increase with decreasing drug-to-polymer weightratio. However, due to the practical limits of keeping the total mass ofa dosage form low, it is often desirable to use a relatively highdrug-to-polymer ratio as long as satisfactory results are obtained. Themaximum drug:polymer ratio that yields satisfactory results varies fromdrug to drug and is best determined in the in vitro and/or in vivodissolution tests described below.

Concentration Enhancement

The polymer used in the solid amorphous dispersion is a“concentration-enhancing polymer,” meaning that it meets at least one,and preferably both, of the following conditions. The first condition isthat the concentration-enhancing polymer increases the maximum drugconcentration (MDC) of the CETP inhibitor in the environment of userelative to a control composition consisting of an equivalent amount ofthe undispersed CETP inhibitor but no polymer. That is, once thecomposition is introduced into an environment of use, the polymerincreases the aqueous concentration of CETP inhibitor relative to thecontrol composition. It is to be understood that the control compositionis free from solubilizers or other components that would materiallyaffect the solubility of the CETP inhibitor, and that the CETP inhibitoris in solid form in the control composition. The control composition isconventionally the undispersed, or crystalline form, of the CETPinhibitor alone. Preferably, the polymer increases the MDC of the CETPinhibitor in aqueous solution by at least 1.25-fold relative to acontrol composition, more preferably by at least 2-fold, and mostpreferably by at least 3-fold. Surprisingly, the polymer may achieveextremely large enhancements in aqueous concentration. In some cases,the MDC of CETP inhibitor provided by the test composition is at least10-fold, at least 50-fold, at least 200-fold, at least 500-fold, to morethan 1000-fold the equilibrium concentration provided by the control.

The second condition is that the concentration-enhancing polymerincreases the area under the concentration in the use environment versustime curve (AUC) of the CETP inhibitor in the environment of userelative to a control composition consisting of the undispersed CETPinhibitor but no polymer. (The calculation of an AUC is a well-knownprocedure in the pharmaceutical arts and is described, for example, inWelling, “Pharmacokinetics Processes and Mathematics,” ACS Monograph 185(1986).) More specifically, in the environment of use, the compositioncomprising the CETP inhibitor and the concentration-enhancing polymerprovides an AUC in the use environment for any 90-minute period of fromabout 0 to about 270 minutes following introduction to the useenvironment that is at least 1.25-fold that of the control compositiondescribed above. Preferably, the AUC in the use environment provided bythe composition is at least 2-fold, more preferably at least 3-fold thatof the control composition. For some CETP inhibitors, the compositionsof the present invention may provide an AUC value that is at least5-fold, at least 25-fold, at least 100—fold, and even more than 250-foldthat of a control composition as described above.

As previously mentioned, a “use environment” can be either the in vivoenvironment, such as the GI tract of an animal, particularly a human, orthe in vitro environment of a test solution, such as phosphate bufferedsaline (PBS) solution or Model Fasted Duodenal (MFD) solution.

Concentration enhancement may be determined through either in vivo testsor through in vitro dissolution tests. A composition of the presentinvention meets the concentration enhancement criteria in at least oneof the above test environments.

Where the use environment is the GI tract of an animal, dissolved drugconcentration may be determined by a conventional method known in theart. One method is a deconvolution method. In this method, the serum orplasma drug concentration is plotted along the ordinate (y-axis) againstthe blood sample time along the abscissa (x-axis). The data may then beanalyzed to determine drug release rates in the GI tract using anyconventional analysis, such as the Wagner-Nelson or Loo-Riegelmananalysis. See also Welling, “Pharmacokinetics: Processes andMathematics” (ACS Monograph 185, Amer. Chem. Soc., Washington, D.C.,1986). Treatment of the data in this manner yields an apparent in vivodrug release profile. Another method is to intubate the patient andperiodically sample the GI tract directly.

The solid amorphous dispersions of CETP inhibitor andconcentration-enhancing polymer used in the inventive dosage formsprovide enhanced concentration of the dissolved CETP inhibitor in vitrodissolution tests. It has been determined that enhanced drugconcentration in vitro dissolution tests in MFD solution or in PBSsolution is a good indicator of in vivo performance and bioavailability.An appropriate PBS solution is an aqueous solution comprising 20 mMNa₂HPO₄, 47 mM KH₂PO₄, 87 mM NaCl, and 0.2 mM KCl, adjusted to pH 6.5with NaOH. An appropriate MFD solution is the same PBS solution whereinthere is also present 7.3 mM sodium taurocholic acid and 1.4 mM of1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine. In particular, acomposition formed by the inventive method can be dissolution-tested byadding it to MFD or PBS solution and agitating to promote dissolution.

An in vitro test to evaluate enhanced CETP inhibitor concentration inaqueous solution can be conducted by (1) adding with agitation asufficient quantity of control composition, typically the undispersedCETP inhibitor alone, to the in vitro test medium, such as an MFD or aPBS solution, to achieve equilibrium concentration of the CETPinhibitor; (2) in a separate vessel, adding with agitation a sufficientquantity of test composition (e.g., the solid amorphous dispersion ofCETP inhibitor and polymer) in the same test medium, such that if allthe CETP inhibitor dissolved, the theoretical concentration of CETPinhibitor would exceed the equilibrium concentration of the CETPinhibitor by a factor of at least 2, and preferably by a factor of atleast 10; and (3) comparing the measured MDC and/or aqueous AUC of thetest composition in the test medium with the equilibrium concentration,and/or with the aqueous AUC of the control composition. In conductingsuch a dissolution test, the amount of test composition or controlcomposition used is an amount such that if all of the CETP inhibitordissolved the CETP inhibitor concentration would be at least 2-fold,preferably at least 10-fold, and most preferably at least 100-fold thatof the equilibrium concentration. Indeed, for some extremely insolubleCETP inhibitors, in order to identify the MDC achieved it may benecessary to use an amount of test composition such that if all of theCETP inhibitor dissolved, the CETP inhibitor concentration would be1000-fold or even more, that of the equilibrium concentration of theCETP inhibitor.

The concentration of dissolved CETP inhibitor is typically measured as afunction of time by sampling the test medium and plotting CETP inhibitorconcentration in the test medium vs. time so that the MDC can beascertained. The MDC is taken to be the maximum value of dissolved CETPinhibitor measured over the duration of the test. The aqueous AUC iscalculated by integrating the concentration versus time curve over any90-minute time period between the time of introduction of thecomposition into the aqueous use environment (when time equals zero) and270 minutes following introduction to the use environment (when timeequals 270 minutes). Typically, when the composition reaches its MDCrapidly, in say less than about 30 minutes, the time interval used tocalculate AUC is from time equals zero to time equals 90 minutes.However, if the AUC of a composition over any 90-minute time perioddescribed above meets the criterion of this invention, then thecomposition formed is considered to be within the scope of thisinvention.

To avoid large drug particulates that would give an erroneousdetermination, the test solution is either filtered or centrifuged.“Dissolved drug” is typically taken as that material that either passesa 0.45 μm syringe filter or, alternatively, the material that remains inthe supernatant following centrifugation. Filtration can be conductedusing a 13 mm, 0.45 μm polyvinylidine difluoride syringe filter sold byScientific Resources under the trademark TITAN®. Centrifugation istypically carried out in a polypropylene microcentrifuge tube bycentrifuging at 13,000 G for 60 seconds. Other similar filtration orcentrifugation methods can be employed and useful results obtained. Forexample, using other types of microfilters may yield values somewhathigher or lower (±10-40%) than that obtained with the filter specifiedabove but will still allow identification of preferred dispersions. Itshould be recognized that this definition of “dissolved drug”encompasses not only monomeric solvated drug molecules but also a widerange of species such as polymer/drug assemblies that have submicrondimensions such as drug aggregates, aggregates of mixtures of polymerand drug, micelles, polymeric micelles, colloidal particles ornanocrystals, polymer/drug complexes, and other such drug-containingspecies that are present in the filtrate or supernatant in the specifieddissolution test.

In another separate aspect, the solid amorphous dispersions, when dosedorally to a human or other animal in a fasted state, provides improvedconcentration of dissolved CETP inhibitor in the blood relative to thecontrol composition. The solid amorphous dispersion achieves a highermaximum drug concentration (C_(max)) of the CETP inhibitor in the blood(serum or plasma) relative to a control composition consisting of anequivalent amount of crystalline drug in its lowest energy form, oramorphous form if the crystalline form is unknown. It is to beunderstood that the control composition is free from solubilizers orother components that would materially affect the solubility of the CETPinhibitor. Preferably, the solid amorphous dispersion provides a C_(max)of CETP inhibitor in the blood that is at least 1.25-fold that providedby the control composition, more preferably by at least 2-fold, and mostpreferably by at least 3-fold.

Alternatively, the solid amorphous dispersions, when dosed orally to ahuman or other animal, provide an AUC in CETP inhibitor concentration inthe blood that is at least about 1.25-fold, preferably at least about2-fold, preferably at least about 3-fold, preferably at least about4-fold, preferably at least about 6-fold, preferably at least 10-fold,and even more preferably at least about 20-fold that observed when acontrol composition consisting of an equivalent quantity of undispersedCETP inhibitor is dosed. It is noted that such compositions can also besaid to have a relative bioavailability of from about 1.25-fold to about20-fold that of the control composition.

Relative bioavailability of CETP inhibitors in the solid amorphousdispersions can be tested in vivo in animals or humans usingconventional methods for making such a determination. An in vivo test,such as a crossover study, may be used to determine whether acomposition of CETP inhibitor and concentration-enhancing polymerprovides an enhanced relative bioavailability compared with a controlcomposition as described above. In an in vivo crossover study a testcomposition of a solid amorphous dispersion of a CETP inhibitor andpolymer is dosed to half a group of test subjects and, after anappropriate washout period (e.g., one week) the same subjects are dosedwith a control composition that consists of an equivalent quantity ofundispersed CETP inhibitor as the test composition (but with no polymerpresent). The other half of the group is dosed with the controlcomposition first, followed by the test composition. The relativebioavailability is measured as the concentration in the blood (serum orplasma) versus time area under the curve (AUC) determined for the testgroup divided by the AUC in the blood provided by the controlcomposition. Preferably, this test/control ratio is determined for eachsubject, and then the ratios are averaged over all subjects in thestudy. In vivo determinations of AUC can be made by plotting the serumor plasma concentration of drug along the ordinate (y-axis) against timealong the abscissa (x-axis). To facilitate dosing, a dosing vehicle maybe used to administer the dose. The dosing vehicle is preferably water,but may also contain materials for suspending the test or controlcomposition, provided these materials do not dissolve the composition orchange the drug solubility in vivo.

Preparation of Dispersions

The solid amorphous dispersions of CETP inhibitor and acidicconcentration-enhancing polymer may be made according to anyconventional process for forming solid amorphous dispersions thatresults in at least a major portion (at least 60%) of the CETP inhibitorbeing in the amorphous state. Such processes include mechanical, thermaland solvent processes. Exemplary mechanical processes include millingand extrusion; melt processes including high temperature fusion,solvent-modified fusion and melt-congeal processes; and solventprocesses including non-solvent precipitation, spray-coating andspray-drying. See, for example, the following U.S. patents, thepertinent disclosures of which are incorporated herein by reference:Nos. 5,456,923 and 5,939,099, which describe forming dispersions byextrusion processes; Nos. 5,340,591 and 4,673,564, which describeforming dispersions by milling processes; and Nos. 5,707,646 and4,894,235, which describe forming dispersions by melt congeal processes.

When the CETP inhibitor has a relatively low melting point, typicallyless than about 200° C. and preferably less than about 150° C., the useof a melt-congeal or melt-extrusion process is advantageous. In suchprocesses, a molten mixture comprising the CETP inhibitor andconcentration-enhancing polymer is rapidly cooled to solidify the moltenmixture to form a solid amorphous dispersion. By “molten mixture” ismeant that the mixture comprising the CETP inhibitor andconcentration-enhancing polymer is heated sufficiently that it becomessufficiently fluid that the CETP inhibitor substantially disperses inone or more of the concentration-enhancing polymers and otherexcipients. Generally, this requires that the mixture be heated to about10C or more above the melting point of the lowest melting excipient orCETP inhibitor in the composition. The CETP inhibitor may exist in themolten mixture as a pure phase, as a solution of CETP inhibitorhomogeneously distributed throughout the molten mixture, or anycombination of these states or those states that lie intermediatebetween them. The molten mixture is preferably substantially homogeneousso that the CETP inhibitor is dispersed as homogeneously as possiblethroughout the molten mixture. When the temperature of the moltenmixture is below the melting point of both the CETP inhibitor and theconcentration-enhancing polymer, the molten excipients,concentration-enhancing polymer, and CETP inhibitor are preferablysufficiently soluble in each other that a substantial portion of theCETP inhibitor disperses in the concentration-enhancing polymer orexcipients. It is often preferred that the mixture be heated above thelower of the melting points of the concentration-enhancing polymer andthe CETP inhibitor. It should be noted that many concentration-enhancingpolymers are amorphous. In such cases, melting point refers to thesoftening point of the polymer. Thus, although the term “melting point”generally refers specifically to the temperature at which a crystallinematerial transitions from its crystalline to its liquid state, as usedherein, the term is used more broadly, referring to the heating of anymaterial or mixture of materials sufficiently that it becomes fluid in amanner similar to a crystalline material in the fluid state.

Generally, the processing temperature may vary from 50° C. up to about200° C. or higher, depending on the melting point of the CETP inhibitorand polymer, the latter being a function of the polymer grade selected.However, the processing temperature should not be so high that anunacceptable level of degradation of the CETP inhibitor or polymeroccurs. In some cases, the molten mixture should be formed under aninert atmosphere to prevent degradation of the CETP inhibitor and/orpolymer at the processing temperature. When relatively high temperaturesare used, it is often preferable to minimize the time that the mixtureis at the elevated temperature to minimize degradation.

The molten mixture may also include an excipient that will reduce themelting temperature of the molten mixture, thereby allowing processingat a lower temperature. When such excipients have low volatility andsubstantially remain in the mixture upon solidification, they generallycan comprise up to 30 wt % of the molten mixture. For example, aplasticizer may be added to the mixture to reduce the meltingtemperature of the polymer. Examples of plasticizers include water,triethylcitrate, triacetin, and dibutyl sebacate. Volatile agents thatdissolve or swell the polymer, such as acetone, water, methanol andethyl acetate, may also be added to reduce the melting point of themolten mixture. When such volatile excipients are added, at least aportion, up to essentially all of such excipients may evaporate in theprocess of or following conversion of the molten mixture to a solidmixture. In such cases, the processing may be considered to be acombination of solvent processing and melt-congealing or melt-extrusion.Removal of such volatile excipients from the molten mixture can beaccomplished by breaking up or atomizing the molten mixture into smalldroplets and contacting the droplets with a fluid so that the dropletsboth cool and lose all or part of the volatile excipient. Examples ofother excipients that can be added to the mixture to reduce theprocessing temperature include low molecular weight polymers oroligomers, such as polyethylene glycol, polyvinylpyrrolidone, andpoloxamers; fats and oils, including mono-, di-, and triglycerides;natural and synthetic waxes, such as Carnauba wax, beeswax,microcrystalline wax, castor wax, and paraffin wax; long chain alcohols,such as cetyl alcohol and stearyl alcohol; and long chain fatty acids,such as stearic acid. As mentioned above, when the excipient added isvolatile, it may be removed from the mixture while still molten orfollowing solidification to form the solid amorphous dispersion.

Virtually any process may be used to form the molten mixture. One methodinvolves melting the concentration-enhancing polymer in a vessel andthen adding the CETP inhibitor to the molten polymer. Another methodinvolves melting the CETP inhibitor in a vessel and then adding theconcentration-enhancing polymer. In yet another method, a solid blend ofthe CETP inhibitor and concentration-enhancing polymer may be added to avessel and the blend heated to form the molten mixture.

Once the molten mixture is formed, it may be mixed to ensure the CETPinhibitor is homogeneously distributed throughout the molten mixture.Such mixing may be done using mechanical means, such as overhead mixers,magnetically driven mixers and stir bars, planetary mixers, andhomogenizers. Optionally, when the molten mixture is formed in a vessel,the contents of the vessel can be pumped out of the vessel and throughan in-line or static mixer and then returned to the vessel. The amountof shear used to mix the molten mixture should be sufficiently high toensure uniform distribution of the CETP inhibitor in the molten mixture.The molten mixture can be mixed from a few minutes to several hours, themixing time depending on the viscosity of the mixture and the solubilityof the CETP inhibitor and the presence of optional excipients in theconcentration-enhancing polymer.

Yet another method of preparing the molten mixture is to use twovessels, melting the CETP inhibitor in the first vessel and theconcentration-enhancing polymer in a second vessel. The two melts arethen pumped through an in-line static mixer or extruder to produce themolten mixture that is then rapidly solidified.

Still another method of preparing the molten mixture is by the use of anextruder, such as a single-screw or twin-screw extruder, both well knownin the art. In such devices, a solid feed of the composition is fed tothe extruder, whereby the combination of heat and shear forces produce auniformly mixed molten mixture, which can then be rapidly solidified toform the solid amorphous dispersion. The solid feed can be preparedusing methods well known in the art for obtaining solid mixtures withhigh content uniformity. Alternatively, the extruder may be equippedwith two feeders, allowing the CETP inhibitor to be fed to the extruderthrough one feeder and the polymer through the other. Other excipientsto reduce the processing temperature as described above may be includedin the solid feed, or in the case of liquid excipients, such as water,may be injected into the extruder using methods well known in the art.

The extruder should be designed so that it produces a molten mixturewith the CETP inhibitor uniformly distributed throughout thecomposition. Various zones in the extruder should be heated toappropriate temperatures to obtain the desired extrudate temperature aswell as the desired degree of mixing or shear, using procedures wellknown in the art.

When the CETP inhibitor has a high solubility in theconcentration-enhancing polymer, a lower amount of mechanical energywill be required to form the solid amorphous dispersion. In the casewhere the melting point of the undispersed CETP inhibitor is greaterthan the melting point of the undispersed concentration-enhancingpolymer, the processing temperature may be below the melting temperatureof the undispersed CETP inhibitor but greater than the melting point ofthe polymer, since the CETP inhibitor will dissolve into the moltenpolymer. When the melting point of the undispersed CETP inhibitor isless than the melting point of the undispersed concentration-enhancingpolymer, the processing temperature may be above the melting point ofthe undispersed CETP inhibitor but below the melting point of theundispersed concentration-enhancing polymer since the molten CETPinhibitor will dissolve in or be absorbed into the polymer.

When the CETP inhibitor has a low solubility in the polymer, a higheramount of mechanical energy may be required to form the solid amorphousdispersion. Here, the processing temperature may need to be above themelting point of the CETP inhibitor and the polymer. As mentioned above,alternatively, a liquid or low-melting point excipient may be added thatpromotes melting or the mutual solubility of the concentration-enhancingpolymer and a CETP inhibitor. A high amount of mechanical energy mayalso be needed to mix the CETP inhibitor and the polymer to form adispersion. Typically, the lowest processing temperature and an extruderdesign that imparts the lowest amount of mechanical energy, i.e., shear,that produces a satisfactory dispersion (substantially amorphous andsubstantially homogeneous) is chosen in order to minimize the exposureof the CETP inhibitor to harsh conditions.

Once the molten mixture of CETP inhibitor and concentration-enhancingpolymer is formed, the mixture should be rapidly solidified to form thesolid amorphous dispersion. By “rapidly solidified” is meant that themolten mixture is solidified sufficiently fast that substantial phaseseparation of the CETP inhibitor and polymer does not occur. Typically,this means that the mixture should be solidified in less than about 10minutes, preferably less than about 5 minutes and more preferably lessthan about 1 minute. If the mixture is not rapidly solidified, phaseseparation can occur, resulting in the formation of CETP inhibitor-richand polymer-rich phases.

Solidification often takes place primarily by cooling the molten mixtureto at least about 100 and preferably at least about 30° C. below it'smelting point. As mentioned above, solidification can be additionallypromoted by evaporation of all or part of one or more volatileexcipients or solvents. To promote rapid cooling and evaporation ofvolatile excipients, the molten mixture is often formed into a highsurface area shape such as a rod or fiber or droplets. For example, themolten mixture can be forced through one or more small holes to formlong thin fibers or rods or may be fed to a device, such as an atomizersuch as a rotating disk, that breaks the molten mixture up into dropletsfrom 1 μm to 1 cm in diameter. The droplets are then contacted with arelatively cool fluid such as air or nitrogen to promote cooling andevaporation.

A useful tool for evaluating and selecting conditions for formingsubstantially homogeneous, substantially amorphous dispersions via amelt-congeal or melt-extrusion process is the differential scanningcalorimeter (DSC). While the rate at which samples can be heated andcooled in a DSC is limited, it does allow for precise control of thethermal history of a sample. For example, the CETP inhibitor andconcentration-enhancing polymer may be dry-blended and then placed intothe DSC sample pan. The DSC can then be programmed to heat the sample atthe desired rate, hold the sample at the desired temperature for adesired time, and then rapidly cool the sample to ambient or lowertemperature. The sample can then be re-analyzed on the DSC to verifythat it was transformed into a substantially homogeneous, substantiallyamorphous dispersion (i.e., the sample has a single Tg). Using thisprocedure, the temperature and time required to achieve a substantiallyhomogeneous, substantially amorphous dispersion for a given CETPinhibitor and concentration-enhancing polymer can be determined.

Another method for forming solid amorphous dispersions is by “solventprocessing,” which consists of dissolution of the CETP inhibitor and oneor more polymers in a common solvent. “Common” here means that thesolvent, which can be a mixture of compounds, will dissolve both theCETP inhibitor and the polymer(s). After both the CETP inhibitor and thepolymer have been dissolved, the solvent is rapidly removed byevaporation or by mixing with a non-solvent. Exemplary processes arespray-drying, spray-coating (pan-coating, fluidized bed coating, etc.),and precipitation by rapid mixing of the polymer and CETP inhibitorsolution with CO₂, water, or some other non-solvent. Preferably, removalof the solvent results in the formation of a substantially homogeneous,solid amorphous dispersion. In such dispersions, the CETP inhibitor isdispersed as homogeneously as possible throughout the polymer and can bethought of as a solid solution of CETP inhibitor dispersed in thepolymer(s), wherein the solid amorphous dispersion is thermodynamicallystable, meaning that the concentration of CETP inhibitor in the polymeris at or below its equilibrium value, or it may be considered to be asupersaturated solid solution where the CETP inhibitor concentration inthe concentration-enhancing polymer(s) is above its equilibrium value.

The solvent may be removed by spray-drying. The term “spray-drying” isused conventionally and broadly refers to processes involving breakingup liquid mixtures into small droplets (atomization) and rapidlyremoving solvent from the mixture in a spray-drying apparatus wherethere is a strong driving force for evaporation of solvent from thedroplets. Spray-drying processes and spray-drying equipment aredescribed generally in Perry's Chemical Engineers' Handbook, pages 20-54to 20-57 (Sixth Edition 1984). More details on spray-drying processesand equipment are reviewed by Marshall, “Atomization and Spray-Drying,”50 Chem. Eng. Prog. Monogr. Series 2 (1954), and Masters, Spray DryingHandbook (Fourth Edition 1985). The strong driving force for solventevaporation is generally provided by maintaining the partial pressure ofsolvent in the spray-drying apparatus well below the vapor pressure ofthe solvent at the temperature of the drying droplets. This isaccomplished by (1) maintaining the pressure in the spray-dryingapparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); or (2) mixingthe liquid droplets with a warm drying gas; or (3) both (1) and (2). Inaddition, at least a portion of the heat required for evaporation ofsolvent may be provided by heating the spray solution.

Solvents suitable for spray-drying can be any organic compound in whichthe CETP inhibitor and polymer are mutually soluble. Preferably, thesolvent is also volatile with a boiling point of 150° C. or less. Inaddition, the solvent should have relatively low toxicity and be removedfrom the solid amorphous dispersion to a level that is acceptableaccording to The International Committee on Harmonization (ICH)guidelines. Removal of solvent to this level may require a subsequentprocessing step such as tray-drying. Preferred solvents include alcoholssuch as methanol, ethanol, n-propanol, iso-propanol, and butanol;ketones such as acetone, methyl ethyl ketone and methyl iso-butylketone; esters such as ethyl acetate and propylacetate; and variousother solvents such as acetonitrile, methylene chloride, toluene,tetrahydrofuran, and 1,1,1-trichloroethane. Lower volatility solventssuch as dimethyl acetamide or dimethylsulfoxide can also be used.Mixtures of solvents, such as 50% methanol and 50% acetone, can also beused, as can mixtures with water, so long as the polymer and CETPinhibitor are sufficiently soluble to make the spray-drying processpracticable. Generally, due to the hydrophobic nature of low-solubilityCETP inhibitors, non-aqueous solvents are preferred, meaning that thesolvent comprises less than about 10 wt % water.

The solvent-bearing feed, comprising the CETP inhibitor and theconcentration-enhancing polymer, can be spray-dried under a wide varietyof conditions and yet still yield dispersions with acceptableproperties. For example, various types of nozzles can be used to atomizethe spray solution, thereby introducing the spray solution into thespray-dry chamber as a collection of small droplets. Essentially anytype of nozzle may be used to spray the solution as long as the dropletsthat are formed are sufficiently small that they dry sufficiently (dueto evaporation of solvent) that they do not stick to or coat thespray-drying chamber wall.

Although the maximum droplet size varies widely as a function of thesize, shape and flow pattern within the spray-dryer, generally dropletsshould be less than about 500 μm in diameter when they exit the nozzle.Examples of types of nozzles that may be used to form the solidamorpohous dispersions include the two-fluid nozzle, the fountain-typenozzle, the flat fan-type nozzle, the pressure nozzle and the rotaryatomizer. In a preferred embodiment, a pressure nozzle is used, asdisclosed in detail in commonly assigned copending U.S. ProvisionalApplication No. 60/353,986, the disclosure of which is incorporatedherein by reference.

The spray solution can be delivered to the spray nozzle or nozzles at awide range of temperatures and flow rates. Generally, the spray solutiontemperature can range anywhere from just above the solvent's freezingpoint to about 20° C. above its ambient pressure boiling point (bypressurizing the solution) and in some cases even higher. Spray solutionflow rates to the spray nozzle can vary over a wide range depending onthe type of nozzle, spray-dryer size and spray-dry conditions such asthe inlet temperature and flow rate of the drying gas. Generally, theenergy for evaporation of solvent from the spray solution in aspray-drying process comes primarily from the drying gas.

The drying gas can, in principle, be essentially any gas, but for safetyreasons and to minimize undesirable oxidation of the CETP inhibitor orother materials in the solid amorphous dispersion, an inert gas such asnitrogen, nitrogen-enriched air or argon is utilized. The drying gas istypically introduced into the drying chamber at a temperature betweenabout 60° and about 300° C. and preferably between about 80° and about240° C.

The large surface-to-volume ratio of the droplets and the large drivingforce for evaporation of solvent leads to rapid solidification times forthe droplets. Solidification times should be less than about 20 seconds,preferably less than about 10 seconds, and more preferably less than 1second. This rapid solidification is often critical to the particlesmaintaining a uniform, homogeneous dispersion instead of separating intoCETP inhibitor-rich and polymer-rich phases. In a preferred embodiment,the height and volume of the spray-dryer are adjusted to providesufficient time for the droplets to dry prior to impinging on aninternal surface of the spray-dryer, as described in detail in commonlyassigned, copending U.S. Provisional Application No. 60/354,080, nowpublished U.S. Patent Application 20030163931, incorporated herein byreference. As noted above, to get large enhancements in concentrationand bioavailability it is often necessary to obtain as homogeneous adispersion as possible.

Following solidification, the solid powder typically stays in thespray-drying chamber for about 5 to 60 seconds, further evaporatingsolvent from the solid powder. The final solvent content of the soliddispersion as it exits the dryer should be low, since this reduces themobility of the CETP inhibitor molecules in the solid amorphousdispersion, thereby improving its stability. Generally, the solventcontent of the solid amorphous dispersion as it leaves the spray-dryingchamber should be less than 10 wt % and preferably less than 2 wt %.Following formation, the solid amorphous dispersion can be dried toremove residual solvent using suitable drying processes, such as traydrying, fluid bed drying, microwave drying, belt drying, rotary drying,and other drying processes known in the art.

The solid amorphous dispersion is usually in the form of smallparticles. The mean size of the particles may be less than 500 μm indiameter, or less than 100 μm in diameter, less than 50 μm in diameteror less than 25 μm in diameter. When the solid amorphous dispersion isformed by spray-drying, the resulting dispersion is in the form of suchsmall particles. When the solid amorphous dispersion is formed by othermethods such by melt-congeal or extrusion processes, the resultingdispersion may be sieved, ground, or otherwise processed to yield aplurality of small particles.

Once the solid amorphous dispersion comprising the CETP inhibitor andconcentration-enhancing polymer has been formed, several processingoperations can be used to facilitate incorporation of the dispersioninto a dosage form. These processing operations include drying,granulation, and milling.

The solid amorphous dispersion may be granulated to increase particlesize and improve handling of the dispersion while forming a suitabledosage form. Preferably, the average size of the granules will rangefrom 50 to 1000 μm. Such granulation processes may be performed beforeor after the composition is dried, as described above. Dry or wetgranulation processes can be used for this purpose. An example of a drygranulation process is roller compaction. Wet granulation processes caninclude so-called low shear and high shear granulation, as well as fluidbed granulation. In these processes, a granulation fluid is mixed withthe composition after the dry components have been blended to aid in theformation of the granulated composition. Examples of granulation fluidsinclude water, ethanol, isopropyl alcohol, n-propanol, the variousisomers of butanol, and mixtures thereof.

If a wet granulation process is used, the granulated composition isoften dried prior to further processing. Examples of suitable dryingprocesses to be used in connection with wet granulation are the same asthose described above. Where the solid amorphous dispersion is made by asolvent process, the composition can be granulated prior to removal ofresidual solvent. During the drying process, residual solvent andgranulation fluid are concurrently removed from the composition.

Once the composition has been granulated, it may then be milled toachieve the desired particle size. Examples of suitable processes formilling the composition include hammer milling, ball milling,fluid-energy milling, roller milling, cutting milling, and other millingprocesses known in the art.

Processes for forming solid amorphous dispersions of CETP inhibitors andconcentration-enhancing polymers are described in detail in commonlyassigned, copending U.S. patent application Ser. Nos. 09/918,127 and10/066,091, incorporated herein by reference.

HMG-CoA Reductase Inhibitors

The HMG-CoA reductase inhibitor may be any HMG-CoA reductase inhibitorcapable of lower plasma concentrations of low-density lipoprotein, totalcholesterol, or both. The HMG-CoA reductase inhibitor is acid-sensitive,meaning that the drug either chemically reacts with or otherwisedegrades in the presence of acidic species. Examples of chemicalreactions include hydrolysis, lactonization, or transesterification inthe presence of acidic species.

In one aspect, the HMG-CoA reductase inhibitor is from a class oftherapeutics commonly called statins. Examples of HMG-CoA reductaseinhibitors that may be used include but are not limited to lovastatin(MEVACOR®; see U.S. Pat. Nos. 4,231,938; 4,294,926; 4,319,039),simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784; 4,450,171, 4,820,850;4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227;4,537,859; 4,410,629; 5,030,447 and 5,180,589), lactones of pravastatin(see U.S. Pat. No. 4,448,979), fluvastatin (LESCOL®; see U.S. Pat. Nos.5,354,772; 4,911,165; 4,739,073; 4,929,437; 5,189,164; 5,118,853;5,290,946; 5,356,896), lactones of fluvastatin, atorvastatin (LIPITOR®;see U.S. Pat. Nos. 5,273,995; 4,681,893; 5,489,691; 5,342,952), lactonesof atorvastatin, cerivastatin (also known as rivastatin and BAYCHOL®;see U.S. Pat. No. 5,177,080, and European Application No. EP-491226A),lactones of cerivastatin, rosuvastatin (Crestor®; see U.S. Pat. Nos.5,260,440 and RE37314, and European Patent No. EP521471), lactones ofrosuvastatin, itavastatin, nisvastatin, visastatin, atavastatin,bervastatin, compactin, dihydrocompactin, dalvastatin, fluindostatin,pitivastatin, mevastatin (see U.S. Pat. No. 3,983,140), and velostatin(also referred to as synvinolin). Other examples of HMG-CoA reductaseinhibitors are described in U.S. Pat. Nos. 5,217,992; 5,196,440;5,189,180; 5,166,364; 5,157,134; 5,110,940; 5,106,992; 5,099,035;5,081,136; 5,049,696; 5,049,577; 5,025,017; 5,011,947; 5,010,105;4,970,221; 4,940,800; 4,866,058; 4,686,237; 4,647,576; EuropeanApplication Nos. 0142146A2 and 0221025A1; and PCT Application Nos. WO86/03488 and WO 86/07054. Also included are pharmaceutically acceptableforms of the above. All of the above references are incorporated hereinby reference. Preferably the HMG-CoA reductase inhibitor is selectedfrom the group consisting of fluvastatin, lovastatin, pravastatin,atorvastatin, simvastatin, cerivastatin, rivastatin, mevastatin,velostatin, compactin, dalvastatin, fluindostatin, rosuvastatin,pitivastatin, dihydrocompactin, and pharmaceutically acceptable formsthereof. By “pharmaceutically acceptable forms” is meant anypharmaceutically acceptable derivative or variation, includingstereoisomers, stereoisomer mixtures, enantiomers, solvates, hydrates,isomorphs, polymorphs, salt forms and prodrugs.

A test to determine whether an HMG-CoA reductase inhibitor is acidsensitive is to administer the drug to an acidic aqueous solution andplot drug concentration versus time. The acidic solution should have apH of from 1-4. HMG-CoA reductase inhibitors that-are acid sensitive arethose for which the drug concentration decreases by at least 1% within24 hours of administration of the drug to the acidic solution. If thedrug concentration changes by 1% in the 6-24 hour time period, then thedrug is “slightly acid-sensitive.” If the drug concentration changes by1% in the 1-6 hour time period, then the drug is “moderatelyacid-sensitive.” If the drug concentration changes by 1% in less than 1hour, then the drug is “highly acid-sensitive.” The present inventionfinds increasing utility for HMG-CoA reductase inhibitors that areslightly acid-sensitive, moderately acid-sensitive and highlyacid-sensitive.

In one embodiment, the HMG-CoA reductase inhibitor is selected from thegroup consisting of trans-6-[2-(3 or 4-carboxamido-substitutedpyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones and corresponding pyranring-opened hydroxy acids derived therefrom. These compounds have beendescribed in U.S. Pat. No. 4,681,893, which is herewith incorporated byreference in the present specification. The pyran ring-opened hydroxyacids which are intermediates in the synthesis of the lactone compoundscan be used as free acids or as pharmaceutically acceptable metal oramine salts. In particular, these compounds can be represented by thefollowing structure:

wherein X is —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—or —CH₂CH(CH₃) —;

-   R₁ is 1-naphthyl; 2-naphthyl; cyclohexyl, norbornenyl; 2-,3-, or    4-pyridinyl; phenyl; phenyl substituted with fluorine, chlorine,    bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon    atoms, alkoxy of from one to four carbon atoms, or alkanoylalkoxy of    from two to eight carbon atoms; either R₂ or R₃ is —CONR₅R₆ where R₅    and R₆ are independently hydrogen; alkyl of from one to six carbon    atoms; 2-,3-, or 4-pyridinyl; phenyl; phenyl substituted with    fluorine, chlorine, bromine, cyano, trifluoromethyl, or carboalkoxy    of from three to eight carbon atoms; and the other of R₂ or R₃ is    hydrogen; alkyl of from one to six carbon atoms; cyclopropyl;    cyclobutyl; cyclopentyl; cyclohexyl; phenyl; or phenyl substituted    with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl    of from one to four carbon atoms, alkoxy of from one to four carbon    atoms, or alkanoyloxy of from two to eight carbon atoms; R₄ is alkyl    of from one to six carbon atoms; cyclopropyl; cyclobutyl;    cyclopentyl; cyclohexyl; or trifluoromethyl; and M is a    pharmaceutically acceptable salt (e.g., counter ion), which includes    a pharmaceutically acceptable metal salt or a pharmaceutically    acceptable amine salt.

Among the stereo-specific isomers, one preferred HMG-CoA reductaseinhibitor is atorvastatin trihydrate hemi-calcium salt. This preferredcompound is the ring-opened form of (2R-trans)-5-(4-fluorophenyl)-2-(1methylethyl)—N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, namely, the enantiomer[R-(R*,R*)]-2-(4-fluorophenyl-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl)]-1H-pyrrole-1-heptanoic acid hemicalcium salt. Its chemical structure may berepresented by the following structure:

The specific isomer has been described in U.S. Pat. No. 5,273,995,herein incorporated by reference. In a preferred embodiment, the HMG-CoAreductase inhibitor is selected from the group consisting ofatorvastatin, the cyclized lactone form of atorvastatin, a 2-hydroxy,3-hydroxy or 4-hydroxy derivative of such compounds, andpharmaceutically acceptable forms thereof.

In practice, use of the salt form amounts to use of the acid or lactoneform. Appropriate pharmaceutically acceptable salts within the scope ofthe invention are those derived from bases such as sodium hydroxide,potassium hydroxide, lithium hydroxide, calcium hydroxide,1-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide,aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide ororganic amines such as N-methylglucamine, choline, arginine and thelike. Preferably, the lithium, calcium, magnesium, aluminum and ferrousor ferric salts are prepared from the sodium or potassium salt by addingthe appropriate reagent to a solution of the sodium or potassium salt,i.e., addition of calcium chloride to a solution of the sodium orpotassium salt of the compound of the formula A will give the calciumsalt thereof.

Preparation of Unitary Dosage Forms

The unitary dosage form is formed by combining a CETP inhibitorcomposition with an HMG-CoA reductase inhibitor composition such thatthe solid amorphous dispersion and the HMG-CoA reductase inhibitor aresubstantially separate from one another in the dosage form. As describedabove, by substantially separate is meant that a sufficient amount ofthe HMG-CoA reductase inhibitor is physically separated from the solidamorphous dispersion so that the acidic concentration-enhancing polymerdoes not cause an unacceptable level of chemical degradation of theHMG-CoA reductase inhibitor. This improved chemical stability of theHMG-CoA reductase inhibitor is believed to be related primarily toreducing the fraction of HMG-CoA reductase inhibitor molecules that arein contact with the CETP inhibitor/acidic concentration-enhancingpolymer solid amorphous dispersion.

For some unitary dosage forms, the separation is macroscopic in nature;that is, the HMG-CoA reductase inhibitor and the solid amorphousdispersion are physically separated. This may be accomplished by, forexample, placing the HMG-CoA reductase inhibitor and the solid amorphousdispersion in separate layers of the dosage form so that only thoseHMG-CoA reductase inhibitor molecules present at the interface of thetwo layers may be in contact with the solid amorphous dispersion.Further separation between the HMG-CoA reductase inhibitor and the solidamorphous dispersion may be obtained by providing a third layer thatseparates the two compositions. Alternatively, the unitary dosage formmay be in the form of a kit wherein the HMG-CoA reductase inhibitor andsolid amorphous dispersion are within separate compartments in thedosage form. Further details of unitary dosage forms where theseparation is macroscopic in nature are described below.

For other unitary dosage forms, the separation is microscopic in nature;that is, the separation may be due to only one or more interveningmolecules. This is the case when the dosage form comprises a mixture ofparticles or granules. For example, the unitary dosage form may comprisethe solid amorphous dispersion of the CETP inhibitor and a plurality ofrelatively large particles or granules comprising the HMG-CoA reductaseinhibitor. The HMG-CoA reductase inhibitor molecules located in theinterior of the particles or granules are separated from the solidamorphous dispersion of the CETP inhibitor by those molecules on thesurface of the particles or granules. Furthermore, inclusion ofexcipients in the particles or granules containing the HMG-CoA reductaseinhibitor will reduce the number of molecules of HMG-CoA reductaseinhibitor on the surface of the particles or granules, resulting infurther separation of the HMG-CoA reductase inhibitor from the solidamorphous dispersion.

Alternatively, the solid amorphous dispersion of CETP inhibitor may bein the form of relatively large particles or granules, with molecules ofthe acidic concentration-enhancing polymer in the solid amorphousdispersion on the interior of the particles of granules being separatedfrom the HMG-CoA reductase inhibitor by those molecules on the surfaceof the particles or granules. Inclusion of granulation excipients in theparticles or granules further reduces the fraction of solid amorphousdispersion on the surface of the particles or granules.

Alternatively, particles or granules of the HMG-CoA reductase inhibitor,particles or granules of the solid amorphous dispersion, or both may becoated with a protective coating, thus separating the HMG-CoA reductaseinhibitor and the solid amorphous dispersion. In any case, the HMG-CoAreductase inhibitor and the solid amorphous dispersion are substantiallyseparated from one another so that the acidic concentration-enhancingpolymer does not cause an unacceptable level of chemical degradation ofthe HMG-CoA reductase inhibitor.

The amount of CETP inhibitor and HMG-CoA reductase inhibitor present inthe dosage form will vary depending on the desired dose for eachcompound, which in turn, depends on the potency of the compound and thecondition being treated. For example, the desired dose for the CETPinhibitor torcetrapib, also known as[2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methdxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester, ranges from 1 mg/day to 1000 mg/day, preferably 10 to250 mg/day, more preferably 30 to 90 mg/day. For the HMG-CoA reductaseinhibitor atorvastatin calcium, the dose ranges from 1 to 160 mg/day,preferably 2 to 80 mg/day. For the HMG-CoA reductase inhibitorslovastatin, pravastatin sodium, simvastatin, rosuvastatin calcium, andfluvastatin sodium, the dose ranges from 2 to 160 mg/day, preferably 10to 80 mg/day. For the HMG-CoA reductase inhibitor cerivastatin sodium,the dose ranges from 0.05 to 1.2 mg/day, preferably 0.1 to 1.0 mg/day.

The CETP inhibitor composition comprises the solid amorphous dispersionand optional excipients, depending on the type of dosage form beingprepared. The amount of solid amorphous dispersion present in the CETPinhibitor composition may vary according to the desired dose of CETPinhibitor. In one aspect, the CETP inhibitor composition has a highloading of the solid amorphous dispersion. High loadings of dispersionin the composition minimize the size of the dosage form, making thedosage form easier to swallow and improving patient compliance.Depending on the CETP inhibitor dose, the solid amorphous dispersion maycomprise at least 30 wt % of the CETP inhibitor composition. Morepreferably, the solid amorphous dispersion comprises at least 40 wt %,and most preferably at least 50 wt % of the CETP inhibitor composition.

In addition to the solid amorphous dispersion, the CETP inhibitorcomposition may also comprise a disintegrant. The inclusion of adisintegrant into the CETP inhibitor composition promotes rapiddissolution of the dosage form when introduced into an aqueous useenvironment. Examples of disintegrants include sodium starch glycolate,sodium carboxymethyl cellulose, calcium carboxymethyl cellulose,croscarmellose sodium, crospovidone, polyvinylpolypyrrolidone, methylcellulose, microcrystalline cellulose, powdered cellulose, loweralkyl-substituted hydroxypropyl cellulose, polacrilin potassium, starch,pregelatinized starch, sodium alginate, and mixtures thereof. Of these,crospovidone, croscarmellose sodium, lower alkyl-substitutedhydroxypropyl cellulose, methyl cellulose, polacrilin potassium, andmixtures thereof are preferred, with crospovidone and croscarmellosesodium being most preferred. The amount of disintegrant included in thedosage form will depend on several factors, including the properties ofthe solid amorphous dispersion, other excipients present in thecomposition, and the desired rate of release of CETP inhibitor from thedosage form. Generally, the disintegrant will comprise from 1 wt % to 25wt %, preferably from 5 wt % to 20 wt % of the CETP inhibitorcomposition.

The CETP inhibitor composition may also include a porosigen. A“porosigen” is a material that, when present in the formulationcontaining the solid amorphous dispersion, leads to a high porosity andhigh strength following compression of the blend into a tablet. Inaddition, preferred porosigens are soluble in an acidic environment withaqueous solubilities typically greater than 1 mg/mL at a pH less thanabout 4. Generally, the predominant deformation mechanism for porosigensunder compression is brittle fracture rather than plastic flow. Examplesof porosigens include acacia, calcium carbonate, calcium sulfate,calcium sulfate dihydrate, compressible sugar, dibasic calcium phosphate(anhydrous and dihydrate), tribasic calcium phosphate, monobasic sodiumphosphate, dibasic sodium phosphate, lactose, magnesium oxide, magnesiumcarbonate, silicon dioxide, magnesium aluminum silicate, maltodextrin,mannitol, methyl cellulose, microcrystalline cellulose, sorbitol,sucrose and xylitol. Of these, microcrystalline cellulose and both formsof dibasic calcium phosphate (anhydrous and dihydrate) are preferred. Aswith the disintegrant selection, the amount of porosigen included in thedosage form will depend on the properties of the solid amorphousdispersion, the disintegrant and the porosigen selected. Generally, theporosigen will comprise from 5 to 70 wt %, and preferably from 10 to 50wt % of the dosage form.

Other conventional formulation excipients may be employed in the CETPinhibitor composition, including those excipients well known in the art,e.g., as described in Remington's Pharmaceutical Sciences (18th ed.1990). Generally, excipients such as surfactants, pH modifiers, fillers,matrix materials, complexing agents, solubilizers, pigments, lubricants,glidants, flavorants, and so forth may be used for customary purposesand in typical amounts without adversely affecting the properties of thecompositions.

One very useful class of excipients is surfactants, preferably presentfrom 0 to 10 wt %. Suitable surfactants include fatty acid and alkylsulfonates; commercial surfactants such as benzalkonium chloride(HYAMINE® 1622 from Lonza, Inc. of Fairlawn, N.J.); dioctyl sodiumsulfosuccinate (DOCUSATE SODIUM from Mallinckrodt Specialty Chemicals ofSt. Louis, Mo.); polyoxyethylene sorbitan fatty acid esters (TWEENO®from ICI Americas Inc. of Wilmington, Del.; LIPOSORB® 0-20 from LipochemInc. of Patterson N.J.; CAPMUL® POE-0 from Abitec Corp. of Janesville,Wis.); natural surfactants such as sodium taurocholic acid,1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, and otherphospholipids and mono- and diglycerides; andpolyoxyethylene-polyoxypropylene. Such materials can advantageously beemployed to increase the rate of dissolution by, for example,facilitating wetting, or otherwise increase the rate of CETP inhibitorrelease from the dosage form.

Inclusion of pH modifiers such as acids, bases, or buffers may also bebeneficial in an amount of from 0 to 10 wt %. Acidic pH modifiers (e.g.,acids such as citric acid or succinic acid) retard the dissolution ofthe solid amorphous dispersion comprising the CETP inhibitor and acidicconcentration-enhancing polymer.

In a preferred embodiment, the CETP inhibitor composition also includesa base. The inclusion of a base can locally raise the pH in the vicinityof the acidic concentration-enhancing polymer, leading to an improvementin chemical stability of the HMG-CoA reductase inhibitor. The term“base” is used broadly to include not only strong bases such as sodiumhydroxide, but also weak bases and buffers that are capable of achievingthe desired increase chemical stability. Examples of bases includehydroxides, such as sodium hydroxide, calcium hydroxide, ammoniumhydroxide, and choline hydroxide; bicarbonates, such as sodiumbicarbonate, potassium bicarbonate, and ammonium bicarbonate;carbonates, such as ammonium carbonate, calcium carbonate, and sodiumcarbonate; amines, such as tris(hydroxymethyl)amino methane,ethanolamine, diethanolamine, N-methyl glucamine, glucosamine,ethylenediamine, N,N′-dibenzylethylenediamine,N-benzyl-2-phenethylamine, cyclohexylamine, cyclopentylamine,diethylamine, isopropylamine, diisopropylamine, dodecylamine, andtriethylamine; proteins, such as gelatin; amino acids such as lysine,arginine, guanine, glycine, and adenine; polymeric amines, such aspolyamino methacrylates, such as Eudragit E; conjugate bases of variousacids, such as sodium acetate, sodium benzoate, ammonium acetate,disodium phosphate, trisodium phosphate, calcium hydrogen phosphate,sodium phenolate, sodium sulfate, ammonium chloride, and ammoniumsulfate; salts of EDTA, such as tetra sodium EDTA; and salts of variousacidic polymers such as sodium starch glycolate, sodium carboxymethylcellulose and sodium polyacrylic acid. In one embodiment, the basepartially neutralizes the acidic concentration-enhancing polymer. By“partially neutralizes” is meant that the base causes at least a portionof the acidic moieties or acidic substituents on the acidicconcentration-enhancing polymer to exist in their deprotonated form.Such neutralized acidic polymers are described in more detail incopending, commonly assigned Provisional Patent Application entitled“Dosage Forms Comprising a CETP Inhibitor and an HMG-CoA ReductaseInhibitor” U.S. provisional patent application No. 60/435,298 filed Dec.20, 2002, the disclosure of which is herein incorporated by reference.In a preferred embodiment, the base is present in an amount that is inmolar excess relative to the acidic substituents on the dispersionpolymer.

Examples of other matrix materials, fillers, or diluents includedextrose, compressible sugar, hydrous lactose, corn starch, silicicanhydride, polysaccharides, dextrates, dextran, dextrin, dextrose,calcium carbonate, calcium sulfate, poloxamers, and polyethylene oxide.

Another optional excipient is a binder such as methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylalcohol or starch.

Examples of drug-complexing agents or solubilizers include polyethyleneglycols, caffeine, xanthene, gentisic acid and cylodextrins.

Examples of lubricants include calcium stearate, glyceryl monostearate,glyceryl palmitostearate, hydrogenated vegetable oil, light mineral oil,magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate,sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc andzinc stearate.

Examples of glidants include silicon dioxide, talc and cornstarch.

The CETP inhibitor composition may be formed according to anyconventional method. In one embodiment, the composition is formed byblending the solid amorphous dispersion and optional excipients usingprocedures well-known in the art (see, for example, Remington'sPharmaceutical Sciences (18th ed. 1990)). Examples of blending equipmentinclude twin-shell blenders, fluidized beds, and V blenders.

In another embodiment, the composition is granulated. Exemplary methodsare wet-granulation and dry-granulation. The solid amorphous dispersionmay be granulated, with or without the addition of other optionalexcipients. For example, the solid amorphous dispersion, a disintegrant,and a porosigen may be granulated by mechanical means by, for example,roller compaction or “slugging,” followed by milling to form granules.The granules typically have improved flow, handling, blending, andcompression properties relative to the ungranulated materials. Wetgranulation techniques may also be employed, provided the solvents andprocess selected do not alter the properties of the solid amorphousdispersion. When wet granulation is used, the granulation liquid istypically removed from the granules during or after the granulationprocess. The so-formed granules typically have an average diameterranging from 50 μm to 1000 μm, preferably 50 μm to about 800 μm,although granules outside this range can be used. Improved wetting,disintegrating, dispersing and dissolution properties may be obtained bythe inclusion of other excipients described above.

In another embodiment, the CETP inhibitor composition comprises thesolid amorphous dispersion coated with a protective coating. The coatingis not acidic and substantially separates the solid amorphous dispersionfrom the HMG-CoA reductase inhibitor. Preferably, the coating materialis aqueous soluble or dispersable in the use environment. Examples ofcoating materials include sugars, such as glucose, sucrose, xylitol,fructose, lactose, mannitol, sorbitol, and maltitol; cellulosicpolymers, such as ethyl cellulose, methyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose;non-cellulosic polymers such as polyethylene glycol, polyethylene oxide,polypropylene glycol, polyethylene-polypropylene glycol copolymers(poloxamers), polyvinyl pyrrolidinone, starch, dextran, dextrin,polydextrose, polyalkenes, polyethers, polyvinyl alcohols, polyvinylhalides, polyvinyl ethers; waxes, such as synthetic wax,microcrystalline wax, paraffin wax, Carnauba wax, and beeswax; andglycerides, such as glyceryl monooleate, glyceryl monostearate, glycerylpalmitostearate, polyethoxylated castor oil derivatives, glyceryl mono-,di- and tribehenates, hydrogenated vegetable oils, glyceryltripalmitate, glyceryl tristearate. Mixtures of coating materials mayalso be used. Preferred coating materials include cellulosic polymerssuch as hydroxylethyl cellulose, hydroxypropyl cellulose, andhydroxypropyl methylcellulose; non-cellulose polymers such aspolyethylene glycol, polyethylene oxide, poloxamers, and polyvinylpyrrolidinone; and mixtures thereof.

The solid amorphous dispersion may be coated using any method known inthe art, including solution coating and hot-melt coating processes. Insolution coating processes, the coating is made by first forming asolution or suspension comprising the coating excipient, a liquid (e.g.,a solvent), and optional coating additives. The coating materials may becompletely dissolved in the liquid, or only dispersed in the liquid asan emulsion or suspension or anywhere in between. Latex dispersions area specific example of an emulsion or suspension that may be useful as acoating solution. The liquid used for the solution should be inert inthe sense that it does not react with or degrade the drug, and bepharmaceutically acceptable. Preferably, the liquid is volatile. By“volatile” is meant that the material has a boiling point of less thanabout 150° C. at ambient pressure, although small amounts of liquidswith higher boiling points can be used and acceptable results stillobtained.

Examples of liquids suitable for use in coating the solid amorphousdispersion include alcohols, such as methanol, ethanol, isomers ofpropanol and isomers of butanol; ketones, such as acetone, methylethylketone and methyl isobutyl ketone; hydrocarbons, such as pentane,hexane, heptane, cyclohexane, methylcyclohexane, octane and mineral oil;ethers, such as methyl tert-butyl ether, ethyl ether and ethylene glycolmonoethyl ether; chlorocarbons, such as chloroform, methylene dichlorideand ethylene dichloride; tetrahydrofuran; dimethylsulfoxide;N-methylpyrrolidinone; acetonitrile; water; and mixtures thereof.

The coating formulation often includes additives to ease application orimprove the durability or stability of the coating. Preferably, anycoating additive used is non-acidic. Examples of coating additivesinclude plasticizers, such as mineral oils, petrolatum, lanolinalcohols, polyethylene glycol, polypropylene glycol, sorbitol andtriethanol amine; pore formers, such as polyethylene glycol, polyvinylpyrrolidone, polyethylene oxide, hydroxyethyl cellulose andhydroxypropylmethyl cellulose; and glidants, such as colloidal silicondioxide, talc and cornstarch.

The coating may be formed on the solid amorphous dispersion bycontacting the dispersion with the coating formulation using standardcoating equipment, such as fluidized bed coaters (e.g., Würster coatersor top-spray coaters, available from Glalt Air Technologies, Inc. ofRamsey, N.J. and from Niro Pharma Systems of Bubendorf, Switzerland) androtary granulators (e.g., CF-Granulator, available from Freund Corp). Insome cases, the solid amorphous dispersion is granulated prior tocoating with the non-acidic coating.

In one method, a Würster fluidized-bed system is used. In this system, acylindrical partition (the Würster column) is placed inside a conicalproduct container in the apparatus. Air passes through a distributionplate located at the bottom of the product container to fluidize thesolid amorphous dispersion, with the majority of the upward moving airpassing through the Würster column. The solid amorphous dispersionparticles are drawn into the Würster column, which is equipped with anatomizing nozzle that sprays the coating formulation upward. The solidamorphous dispersion particles are coated as they pass through theWurster column, with the liquid being removed as the dispersionparticles exit the column.

Alternatively, a top-spray method can be used to apply the coating. Inthis method, the coating formulation is sprayed down onto the fluidizeddispersion particles. The liquid evaporates from the coated dispersionparticles and the coated dispersion particles are re-fluidized in theapparatus. Coating continues until the desired coating thickness isachieved. Generally, it is preferred that the coating be at least 1 μmthick, preferably at least 5 μm thick, and more preferably at least 10μm thick.

In another method, the coating is applied to the solid amorphousdispersion using a wet-granulation technique. In this method, thecoating material is first dissolved or suspended in a granulation fluid.This granulation mixture is then sprayed onto or mixed with the solidamorphous dispersion, resulting in a thin layer of the coating materialon the outside surface of the resulting granules. The granulation fluidis removed from the granules in a subsequent drying step.

The coating may also be applied using a hot-melt coating technique. Inthis method, the coating excipients and additives are first melted andthen sprayed onto the dispersion particles. Typically, the hot-meltcoating is applied in a fluidized bed equipped with a top-sprayarrangement.

Another method for applying a hot-melt coating to the solid amorphousdispersion particles is to use a modified melt-congeal method. In thismethod, the dispersion particles are suspended in the molten coatingexcipients, the melting point of the dispersion being greater than themelting point of the coating excipients. This suspension is then formedinto droplets comprising dispersion particles substantially surroundedby the coating excipients. The droplets are typically formed through theuse of an atomizer, such as a rotary or spinning-disk atomizer. Thedroplets are then cooled to congeal the coating excipients, forming thecoated dispersion.

The coating may also be applied in a rotary granulator. In such devices,horizontal discs rotate at high speed, forming a rotating “rope” ofdispersion particles at the walls of the vessel. The coating is sprayedinto this rope, coating the solid amorphous dispersion. This techniquecan be used with hot-melt and liquid-based coating solutions.

The HMG-CoA reductase inhibitor composition comprises the HMG-CoAreductase inhibitor and optional excipients, depending on the dosageform being prepared. The amount of the HMG-CoA reductase inhibitor mayvary according to the desired dose of HMG-CoA reductase inhibitor.Preferably, the HMG-CoA reductase inhibitor is crystalline. The HMG-CoAreductase composition preferably stabilizes the HMG-CoA reductaseinhibitor, particularly from degradation due to the presence of acidicmaterials in the dosage form or processing environment, as well asprotects the HMG-CoA reductase inhibitor from photochemicaldecomposition during storage.

In a preferred embodiment, the HMG-CoA reductase inhibitor compositioncomprises a stabilizing agent. The stabilizing agent stabilizes theHMG-CoA reductase inhibitor by reducing acid catalyzed degradation. Thestabilizing agent may be a basic inorganic pharmaceutically acceptablesalt. Exemplary salts include: salts of calcium, such as calciumcarbonate and calcium hydroxide; salts of magnesium, such as magnesiumcarbonate, magnesium hydroxide, magnesium oxide, magnesium silicate,magnesium aluminate, and aluminum magnesium hydroxide; salts of lithium,such as lithium hydroxide and similar lithium compounds; or, othersimilarly suitable salts of alkaline earth metals. The basic inorganicsalts of calcium, lithium or magnesium can be utilized in a weight ratioranging between about 0.1 to 1 and about 50 to 1 of salt compound toactive ingredient.

A preferred stabilizing agent is calcium carbonate. The inventors haveobserved that the size of the calcium carbonate particles is relative tothe effectiveness of calcium carbonate as a stabilizing agent, withsmaller particles size resulting in better performance as a stabilizingagent. Preferred grades of calcium carbonate are precipitated grades ofcalcium carbonate having a particle size of less than about ten microns(μm). Exemplary grades of precipitated calcium carbonate includeVicality Medium PCC and Vicality Heavy PCC available from SpecialtyMinerals, Pre-carb 15 available from Mutchler, and PCC-250 availablefrom Particle Dynamics.

The HMG-CoA reductase composition may also include, in addition to astabilizing metal or alkaline earth metal salt, additional excipientswhich are known as suitable agents in the art comprising combinationsand concentrations as further described below. In a preferredembodiment, the HMG-CoA reductase composition contains conventionaladditional materials suitable for forming a tablet. Such excipientsinclude a diluent, binder, and disintegrant. Antioxidants can also beincorporated into the HMG-CoA reductase inhibitor composition to preventany oxidation of the drug compound. For example, antioxidants that couldbe used are butylated hydroxyanisole, sodium ascorbate, butylatedhydroxytoluene, sodium metabisulfate, malic acid, citric acid andascorbic acid.

In one HMG-CoA reductase inhibitor composition, the compositioncomprises a stabilizing agent, diluents, disintegrant, and surfactant.The basic excipient, calcium carbonate, has been found to chemicallystabilize HMG-CoA reductase inhibitors, such as atorvastatin calcium.Microcrystalline cellulose and hydrous lactose are applied as suitablediluents. Croscarmellose sodium is present as a disintegrant. Thenon-ionic detergent Tween 80 is used as a surfactant. The compositionalso contains hydroxypropyl cellulose as binder selected from amongseveral applicable substances such as, i.e., polyethylene glycol,polyvinylpyrrolidone, polyvinyl alcohol, hydroxymethylcellulose orhydroxypropylmethylcellulose. As anti-oxidants, reagents such asbutylated hydroxyanisole, sodium ascorbate, ascorbic acid or others mayoptionally be incorporated in the composition. Magnesium stearate can beselected from a group including other substances such as stearic acid,palmitic acid, talc or similar lubricating compounds.

Other possible and supplemental ingredients such as preservatives,dryers, glidants, or colorants known as conventional by those skilled inthe art may be included optionally in the HMG-CoA reductase inhibitorcomposition.

In one aspect, the HMG-CoA reductase inhibitor composition comprises thefollowing concentration ranges of ingredients by weight: the HMG-CoAreductase inhibitor is in the range from about 1% to about 50%; calciumcarbonate from about 5% to about 75%; microcrystalline cellulose fromabout 5% to about 75%; hydrous lactose from about 1% to about 80%;croscarmellose sodium from about 1% to about 15%; hydroxypropylcellulosefrom about 0.5% to about 6%; Tween 80 from about 0.1% to about 4%;magnesium stearate from about 0.25% to about 2%; and sodium ascorbatefrom about 0.0% to about 3%.

A more preferred HMG-CoA reductase inhibitor composition comprises thefollowing approximate concentrations of ingredients by weight: about13.9 wt % of the HMG-CoA reductase inhibitor atorvastatin hemicaciumtrihydrate; about 42.4 wt % of calcium carbonate; about 17.7 wt %microcrystalline cellulose; about 19.2 wt % pregelatanized starch; about2.5 wt % hydroxypropyl cellulose; and about 0.5 wt % Tween 80.

The HMG-CoA reductase inhibitor composition may be formed by anyconventional method for combining the HMG-CoA reductase inhibitor andexcipients. Exemplary methods include wet and dry granulation. If wetgranulation is used, a stabilizing agent such as calcium carbonate ispreferably included to keep chemical degradation of the HMG-CoAreductase inhibitor at an acceptable level.

One exemplary method for forming the HMG-CoA reductase inhibitorcomposition comprises (a) milling an excess of the drug, (b) dissolvingat least one binder additive in aqueous surfactant solution; (c)blending the milled drug with at least one drug-stabilizing additive andat least one diluent additive with the drug-stabilizing additive and onehalf of a disintegrant additive in a rotary mixing vessel equipped witha chopping device; (d) granulating the blended drug ingredient mixtureof step (c) with the surfactantibinder solution of step (b) in gradualincrements in the chopper equipped mixing vessel; (e) drying thegranulated drug mixture overnight at about 500C; (f) sieving the driedgranulated drug mixture; (g) tumble blending the sieved drug mixturewith the remaining amount of the disintegrant additive; (h) mixingseparately an aliquot of the drug mixture of step (g) with magnesiumstearate, sieving same, and returning same to the drug mixture of step(g) and tumble blending the entire drug mixture.

In another embodiment, the HMG-CoA reductase inhibitor compositioncomprises the HMG-CoA reductase inhibitor coated with a protectivecoating. In this embodiment, crystals of the HMG-CoA reductase inhibitoror granules comprising the HMG-CoA reductase inhibitor and optionalexcipients are coated with a protective coating. The same protectivecoatings and coating methods described above for applying a protectivecoating to the solid amorphous dispersion may be used to coat theHMG-CoA reductase inhibitor.

The unitary dosage form is formed by combining the CETP inhibitorcomposition with the HMG-CoA reductase inhibitor composition such thatthe solid amorphous dispersion and HMG-CoA reductase inhibitor aresubstantially separate in the dosage form.

In one embodiment, the CETP inhibitor composition and HMG-CoA reductaseinhibitor composition are blended together and then compressed to formthe dosage form, such as tablets, caplets, or pills. Virtually anyprocess can be used to blend the compositions, provided the solidamorphous dispersion and the HMG-CoA reductase inhibitor remainsubstantially separate in the dosage form. For example, the compositionscan be blended in rotating shell mixers, fixed-shell mixers, planetarypaddle mixers, and twin-shell mixers, all known in the art.

The compressed dosage forms may be formed using any of a wide variety ofpresses used in the fabrication of pharmaceutical dosage forms. Examplesinclude single-punch presses, rotary tablet presses, and multilayerrotary tablet presses, all well-known in the art. See Remington'sPharmaceutical Sciences (18^(th) Edition, 1990). The compressed dosageform may be of any shape, including round, oval, oblong, cylindrical, ortriangular. The upper and lower surfaces of the compressed dosage formmay be flat, round, concave, or convex.

When formed by compression, the dosage form preferably has a “strength”of at least 5 Kiloponds (Kp)/cm², and more preferably at least 7 Kp/cm².Here, “strength” is the fracture force, also known as the tablet“hardness,” required to fracture a tablet formed from the materials,divided by the maximum cross-sectional area of the tablet normal to thatforce. The fracture force may be measured using a Schleuniger TabletHardness Tester, model 6D. To achieve the desired strength, the blend ofthe CETP inhibitor composition and HMG-CoA reductase inhibitorcomposition should be compressed with sufficient force while forming thedosage form while ensuring the solid amorphous dispersion and HMG-CoAreductase inhibitor remain substantially separate in the dosage form.The compression force required to achieve this strength will depend onthe size of the tablet, but generally will be greater than about 5kP/cm². Friability is a well-known measure of a dosage form's resistanceto surface abrasion that measures weight loss in percentage aftersubjecting the dosage form to a standardized agitation procedure.Friability values of from 0.8 to 1.0% are regarded as constituting theupper limit of acceptability. Dosage forms having a strength of greaterthan 5 kP/cm² generally are very robust, having a friability of lessthan 0.5%, preferably less than 0.1%.

In some embodiments, the unitary dosage form also comprises a separatinglayer that physically separates the CETP inhibitor composition from theHMG-CoA reductase inhibitor composition. The separating layer ispreferably non acidic. Examples of suitable materials for use in theseparating layer include those listed above as being suitable for use informing a protective coating around the solid amorphous dispersion.

In one embodiment, the unitary dosage form comprises a first granulationcomprising the solid amorphous dispersion of the CETP inhibitor and theacidic concentration-enhancing polymer mixed with a second granulationcomprising the HMG-CoA reductase inhibitor, shown schematically asdosage form 50 in FIG. 5. Here, the CETP inhibitor granulation 52 ismixed with the HMG-CoA reductase inhibitor granulation 54 and thencompressed into the unitary dosage form.

The following process may be used to form such a compressed unitarydosage form. First, the granules of the CETP inhibitor composition areprepared. For example, a solid amorphous dispersion containing about 25wt % of the CETP inhibitor [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester in a concentration-enhancing polymer, such ashydroxypropylmethyl cellulose acetate succinate (HPMCAS), may beprepared via a spray drying process. Next, about 60.15 wt % of the solidamorphous dispersion, about 14.79 wt % of microcrystalline cellulose,and about 10.03 wt % of crospovidone may be blended for 15 minutes in,for example, a twin-shell blender. Next, about 0.25 wt % magnesiumstearate is added and the mixture blended for another 5 minutes. Theblend may then be densified using a roller compactor. The size of thecompacts may then be reduced by milling. Next, about 14.78 wt % dibasiccalcium phosphate anhydrous is added and blended for about 5 minutes ina twin-shell blender, forming the granules of the CETP inhibitorcomposition with an average particle size of about 140 μm.

Next, the granules of the HMG-CoA reductase inhibitor composition areprepared. For example, about 13.9 wt % of the HMG-CoA reductaseinhibitor atorvastatin hemicacium trihydrate; about 42.4 wt % of calciumcarbonate; about 17.7 wt % microcrystalline cellulose; and about 19.2 wt% pregelatanized starch may be fluidized in a fluidized bed granulator.An aqueous solution containing about 2.5 wt % hydroxypropyl celluloseand about 0.5 wt % Tween 80 is then sprayed into the bed to formgranules. The granules are then dried in the bed to remove thegranulation water. The size of the granules may then be reduced bymilling to form granules with a mean granule size of about 110 μm.

To form a unitary dosage form comprising 60 mgA of the CETP inhibitorand 40 mgA of the HMG-CoA reductase inhibitor, 399 mg of the CETPinhibitor granules and the 313 mg of the HMG-CoA reductase inhibitorgranules are then blended in a twin shell blender for 10 minutes. Next,1.8 mg of the lubricant magnesium stearate is added to the mixture andblended for and additional 5 minutes. Compressed tablets containing713.78 mg of material are then formed using a 0.3301-inch (0.8385-cm) by0.6603-inch (1.6772-cm) modified oval tooling. Compression to 20 kNresults in a tablet with a hardness of 8.2 kP. Based on a tablet crosssectional area of 1.1 cm², this corresponds to a tablet strength of 7.5kP/cm².

Alternatively, the mixture of the two compositions described above maybe filled into a capsule, such as a hard- or soft-gelatin capsule or acapsule made from some other material, e.g., starch, to form the unitarydosage form.

In another embodiment, the unitary dosage form may be formed by thefollowing process. First, the HMG-CoA reductase inhibitor may be mixedwith excipients and granulated using a dry- or wet-granulation techniqueto form granules of the HMG-CoA reductase inhibitor composition. TheHMG-CoA reductase inhibitor composition granules may then be mixed withthe solid amorphous dispersion comprising the CETP inhibitor and theacidic concentration-enhancing polymer and optional excipients and theresulting mixture granulated using dry- or wet-granulation techniques.The resulting granules comprising the HMG-CoA reductase inhibitorcomposition and the CETP inhibitor composition may then be compressedinto a tablet, caplet or pill, or the granules may be filled into acapsule, such as a hard- or soft-gelatin capsule.

In another embodiment, the unitary dosage form may be formed by thefollowing process. First, the solid amorphous dispersion comprising theCETP inhibitor and the acidic concentration-enhancing polymer may bemixed with optional excipients and granulated using a dry- orwet-granulation technique to form granules of the CETP inhibitorcomposition. The CETP inhibitor composition granules may then be mixedwith the HMG-CoA reductase inhibitor and optional excipients and theresulting mixture granulated using dry- or wet-granulation techniques.The resulting granules comprising the HMG-CoA reductase inhibitorcomposition and the CETP inhibitor composition may then be compressedinto a tablet, caplet or pill, or the granules may be filled into acapsule, such as a hard- or soft-gelatin capsule.

In another embodiment, the unitary dosage form may be formed by thefollowing process. First, the HMG-CoA reductase inhibitor compositionmay be compressed into a tablet, caplet, or pill. The resultingcompressed tablet, caplet, or pill may then be placed into a capsulealong with the CETP inhibitor composition. Alternatively, the CETPinhibitor composition may first be compressed into a tablet, caplet, orpill. The resulting compressed tablet, caplet, or pill may then beplaced into a capsule along with the HMG-CoA reductase inhibitorcomposition.

In another embodiment, the unitary dosage form may be formed by thefollowing process. First, the HMG-CoA reductase inhibitor compositionmay be formed into multiparticulates using processes well known in theart, such as by extrusion spheronization, cryogenic pelletization, spraydrying, or melt congealing. See, for example, Remington: The Science andPractice of Pharmacy, 20^(th) Edition (2000). The resultingmultiparticulates may then be placed into a capsule along with the CETPinhibitor composition. Alternatively, the CETP inhibitor composition mayfirst be formed into multiparticulates and placed into a capsule alongwith the HMG-CoA reductase inhibitor composition. In another method, theHMG-CoA reductase inhibitor composition may be formed intomultiparticulates and the CETP inhibitor composition may be formed intomultiparticulates, which are then mixed and placed into a capsule.

In another embodiment, the unitary dosage form is in the form of a kit.The kit comprises two separate compositions: (1) one containing thesolid amorphous dispersion comprising a CETP inhibitor and an acidicconcentration-enhancing polymer, and (2) one containing the HMG-CoAreductase inhibitor. The kit is designed such that the HMG-CoA reductaseinhibitor and the solid amorphous dispersion are substantially separate.The kit includes means for containing the separate compositions such asa divided container, such as a bottle, pouch, box, bag or othercontainer known in the art, or a divided foil packet; however, theseparate compositions may also be contained within a single, undividedcontainer. An example of this type of kit is a blister pack wherein eachindividual blister contains two (or more) tablets, one (or more)tablet(s) comprising the CETP inhibitor composition, and the second (ormore) tablet(s) comprising the HMG-CoA reductase inhibitor composition.In one embodiment, the HMG-CoA reductase inhibitor composition is in theform of a compressed tablet. In another embodiment, the CETP inhibitorcomposition is in the form of a compressed tablet. In anotherembodiment, the HMG-CoA reductase inhibitor composition is in the formof multiparticulates. In another embodiment, the CETP inhibitorcomposition is in the form of multiparticulates. Typically the kitincludes directions for the administration of the separate components.

Thus, in one embodiment, the unitary dosage form comprises a kit, thekit comprising (1) a therapeutically effective amount of a CETPinhibitor in a CETP inhibitor composition; (2) a therapeuticallyeffective amount of an HMG-CoA reductase inhibitor in an HMG-CoAreductase inhibitor composition; and (3) a container for containing theCETP inhibitor composition and the HMG-CoA reductase inhibitorcomposition.

An example of such a kit, alluded to above, is a so-called blister pack.Blister packs are well known in the packaging industry and are widelyused for the packaging of pharmaceutical unit dosage forms such astablets, capsules, and the like. Blister packs generally consist of asheet of relatively stiff material covered with a foil of a preferablytransparent plastic material. During the packaging process recesses areformed in the plastic foil. The recesses have the size and shape of thetablets or capsules to be packed. Next, the tablets or capsules areplaced in the recesses and the sheet of relatively stiff material issealed against the plastic foil at the face of the foil which isopposite from the direction in which the recesses were formed. As aresult, the tablets or capsules are sealed in the recesses between theplastic foil and the sheet. Preferably, the strength of the sheet issuch that the tablets or capsules can be removed from the blister packby manually applying pressure on the recesses whereby an opening isformed in the sheet at the place of the recess. Tablet(s) or capsule(s)can then be removed via said opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen during which the tablets orcapsules so specified should be ingested. Another example of such amemory aid is a calendar printed on the card, e.g., as follows “FirstWeek, Monday, Tuesday, . . . etc. . . . . Second Week, Monday, Tuesday,. . . ”, etc. Other variations of memory aids will be readily apparent.

Coatings

The unitary dosage form may optionally be coated with a conventionalcoating well known in the art. The coatings may be used to mask taste,improve appearance, facilitate swallowing of the dosage form, or todelay, sustain or otherwise control the release of the drug from thedosage form. Such coatings may be fabricated by any conventional meansincluding fluidized bed coating, spray-coating, pan-coating andpowder-coating using aqueous or organic solvents. Examples of suitablecoating materials include sucrose, maltitol, cellulose acetate, ethylcellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,polymethacrylates, polyacrylates, polyvinyl alcohol, polyvinylpyrrolidone, cetyl alcohol, gelatin, maltodextrin, paraffin wax,microcrystalline wax, and Carnauba wax. Mixtures of polymers may also beused. Preferred coatings include the commercial aqueous coatingformulations Surelease® and Opadry® available from Colorcon Inc. (WestPoint, Pa.).

In some cases, to avoid poor toleration or to avoid degradation, it isdesired that drugs in the unitary dosage form not be released in thestomach. In these instances, the dosage form may also be overcoated withone or more pH-sensitive coating compositions, commonly referred to inthe pharmaceutical arts as “enteric” coatings, by conventionalprocedures in order to delay the release of drug until it reaches theduodenum or small intestine. pH-sensitive polymers suitable as entericcoatings include those which are relatively insoluble and impermeable atthe pH of the stomach, but which are more soluble or disintegrable orpermeable at the pH of the duodenum and small intestine. SuchpH-sensitive polymers include polyacrylamides, phthalate derivativessuch as acid phthalate of carbohydrates, amylose acetate phthalate,cellulose acetate phthalate (CAP), other cellulose ester phthalates,cellulose ether phthalates, hydroxypropylcellulose phthalate (HPCP),hydroxypropyl ethylcellulose phthalate (HPECP), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCAS, methylcellulose phthalate(MCP), polyvinyl acetate phthalate (PVAcP), polyvinyl acetate hydrogenphthalate, sodium CAP, starch acid phthalate, cellulose acetatetrimellitate (CAT), styrene-maleic acid dibutyl phthalate copolymer,styrene-maleic acid/polyvinylacetate phthalate copolymer, styrene andmaleic acid copolymers, polyacrylic acid derivatives such as acrylicacid and acrylic ester copolymers, polymethacrylic acid and estersthereof, polyacrylic and methacrylic acid copolymers, shellac andcopolymers of vinyl acetate and crotonic acid.

A preferred group of pH-sensitive polymers includes CAP, PVAcP, HPMCP,HPMCAS, anionic acrylic copolymers of methacrylic acid andmethylmethacrylate, and copolymers of acrylic acid and at least oneacrylic acid ester.

To apply the pH-sensitive coating to the dosage form, the pH-sensitivepolymer is first dissolved or suspended in a suitable solvent to form acoating solution. Useful solvents for this purpose include ketones, suchas acetone; alcohols, such as methanol, ethanol, isopropyl alcohol,n-propyl alcohol, and the various isomers of butanol; chlorinatedhydrocarbons, such as methylene chloride; water; and mixtures of thesesolvents. The polymer may also be suspended in the solvent. The coatingsolution may also comprise a latex of the pH-sensitive polymer suspendedin an aqueous solution.

The coating solution may also contain one or more plasticizers, such aspolyethylene glycols, triethyl citrate, propylene glycols, diethylphthalate, dibutyl phthalate, castor oil, triacetin and others known inthe art. The coating solution may also contain one or more emulsifiers,such as polysorbate-80. Coating is conducted in conventional fashion,typically by dipping, spray-coating, or pan-coating.

The coating solution may also contain a base or buffer, such as thosediscussed above. Use of a base or buffer will ensure the pH of thecoating solution is not so low as to increase chemical degradation ofthe HMG-CoA reductase inhibitor. Use of a base or buffer may also beused to minimize reaction of the coating formulation with otherexcipients in the dosage form.

The unitary dosage forms of the present invention may be used to treatany condition, which is subject to treatment by administering a CETPinhibitor and an HMG-CoA reductase inhibitor, as disclosed in commonlyassigned, copending U.S. Patent Application No. 2002/0035125A1. Thedisclosure of which is herein incorporated by reference.

In one aspect, the unitary dosage forms of the present invention areused for antiatherosclerotic treatment.

In another aspect, the unitary dosage forms of the present invention areused for slowing and/or arresting the progression of atheroscleroticplaques.

In another aspect, the unitary dosage forms of the present invention areused for slowing the progression of atherosclerotic plaques in coronaryarteries.

In another aspect, the unitary dosage forms of the present invention areused for slowing the progression of atherosclerotic plaques in carotidarteries.

In another aspect, the unitary dosage forms of the present invention areused for slowing the progression of atherosclerotic plaques in theperipheral arterial system.

In another aspect, the unitary dosage forms of the present invention,when used for treatment of atherosclerosis, causes the regression ofatherosclerotic plaques.

In another aspect, the unitary dosage forms of the present invention areused for regression of atherosclerotic plaques in coronary arteries.

In another aspect, the unitary dosage forms of the present invention areused for regression of atherosclerotic plaques in carotid arteries.

In another aspect, the unitary dosage forms of the present invention areused for regression of atherosclerotic plaques in the peripheralarterial system.

In another aspect, the unitary dosage forms of the present invention areused for HDL elevation treatment and antihyperlipidemic treatment(including LDL lowering).

In another aspect, the unitary dosage forms of the present invention areused for antianginal treatment.

In another aspect, the unitary dosage forms of the present invention areused for cardiac risk management.

Other features and embodiments of the invention will become apparentfrom the following examples, which are given for illustration of theinvention, rather than for limiting its intended scope.

EXAMPLES Example 1

A granulation of the HMG-CoA reductase inhibitor atorvastatin and agranulation of a solid amorphous dispersion containing a CETP inhibitorand a concentration-enhancing polymer were each formed separately. Thetwo granulations were combined and stored at 50° C. and 75% relativehumidity for 3 weeks. The stability of atorvastatin was measured andfound to be improved relative to a control composition.

The following process was used to form a spray-dried dispersioncontaining 25 wt % [2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (torcetrapib) and 75 wt % hydroxypropylmethyl celluloseacetate succinate (medium granular grade available from Shin Etsu,located in Japan) (referred to herein as “HPMCAS-MG”). First, a spraysolution was formed containing 25 g torcetrapib, 75 g HPMCAS-MG, and 900g acetone. The spray solution was pumped using a high-pressure pump(Zenith Z-Drive 2000 High-Pressure Gear Pump) to a spray drier (Nirotype XP Portable Spray-Dryer with a Liquid-Feed Process Vessel [PSD-1])equipped with a pressure atomizer (Spraying Systems Pressure Nozzle andBody (SK 79-16)). The PSD-1 was equipped with a 9-inch chamberextension. The spray drier was also equipped with a diffuser platehaving a 1% open area. The nozzle sat flush with the diffuser plateduring operation. The spray solution was pumped to the spray drier atabout 185 gm/min, with an atomization pressure of about 280 psi. Dryinggas (nitrogen) was circulated through the diffuser plate at an inlettemperature of about 98° C. The evaporated solvent and wet drying gasexited the spray drier at a temperature of 31±4° C. The spray-drieddispersion formed by this process was collected in a cyclone, and had abulk specific volume of about 5 cm³/gm. The solid amorphous dispersionwas post-dried using a Gruenberg single-pass convection tray dryeroperating at 40° C. for about 16 hours.

The spray-dried solid amorphous dispersion was evaluated in an in vitrodissolution test using a microcentrifuge method. In this test, 7.2 mg ofthe spray-dried solid amorphous dispersion was placed into amicrocentrifuge tube. The tube was placed in a 37° C. sonicating bath,and 1.8 mL phosphate buffered saline (PBS) at pH 6.5 and 290 mOsm/kg wasadded, resulting in a torcetrapib concentration of 1000 μg/mL if all ofthe drug had dissolved. The sample was quickly mixed using a vortexmixer for about 60 seconds. The sample was centrifuged at 13,000 G at37° C. for 1 minute. The resulting supernatant solution was then sampledand diluted 1:6 (by volume) with methanol and then analyzed byhigh-performance liquid chromatography (HPLC). The contents of the tubewas mixed on the vortex mixer and allowed to stand undisturbed at 37° C.until the next sample was taken. Samples were collected at 4, 10, 20,40, 90, and 1200 minutes. The concentrations of drug obtained in thesesamples are shown in Table 1, which represent the average of duplicatetests.

As a control, an in vitro dissolution test was performed using theprocedures described above except that 1.8 mg of crystalline drug wasused. The concentrations of drug obtained in vitro dissolution tests areshown in Table 1.

TABLE 1 Torcetrapib Time Concentration AUC Sample (min) (μg/mL)(min-μg/mL) Solid 0 0 0 Amorphous 4 328 660 Dispersion 10 701 3,700 20781 11,200 40 805 27,000 90 780 66,600 1200 439 743,200 Crystalline Drug0 0 0 4 <1 <2 10 <1 <8 20 <1 <18 40 <1 <38 90 <1 <88 1200 <1 <1,200

The results of these dissolution tests are summarized in Table 2, whichshows the maximum concentration of torcetrapib in solution during thefirst 90 minutes of the test (MDC₉₀), the area under the aqueousconcentration versus time curve after 90 minutes (AUC₉₀), and theconcentration at 1200 minutes (C₁₂₀₀).

TABLE 2 Torcetrapib Conc. Aqueous- in the AUC₉₀ Soluble DispersionReceptor MDC₉₀ (min- Sample Polymer (wt %) Solution (μg/mL) μg/mL) C₁₂₀₀(μg/mL) Solid HPMCAS-MF 25 PBS 805 66,600 439 Amorphous DispersionCrystalline None NA PBS <1 <88 <1 Drug

The results summarized in Table 2 show that the solid amorphousdispersion provided concentration enhancement relative to crystallinedrug. The solid amorphous dispersion provided a C_(max.90) value thatwas greater than 805-fold that of the crystilline drug, and the AUC₉₀value that was greater than 756-fold that of the crystalline drug.

A granulation of the above torcetrapib dispersion was made with thefollowing composition: 60 wt % solid amorphous dispersion; 14.8 wt %,microcrystalline cellulose (Avicel PH105, available from FMC Corp.,Philadelphia, Pa.); 10.0 wt %, crospovidone (Polyplasdone, availablefrom International Specialty Products, Wayne, N.J.); 14.8 wt %, dibasiccalcium phosphate anhydrous (A-Tab, available from Rodia, Inc.,Cranbury, N.J.); and 0.5 wt %, and magnesium stearate. First, the solidamorphous dispersion, microcrystalline cellulose, and crospovidone wereadded to an 8 quart twinshell blender and blended for 15 minutes. Halfof the magnesium stearate was added, and the mixture was blended for 5minutes. The mixture was roller-compacted using a TF-mini rollercompactor with a roller pressure of 450 psi, a roller speed of 4 rpm, anauger speed of 25 rpm, and a target ribbon thickness of 0.07 to0.08-inches. The mixture was then milled using an M5A mill with a 0.033inch Conidur screen, at 500 rpm, with the bar head in the knifedirection. Next, the granulation was added to an 8 quart twin shellblender and blended for 15 minutes. Dicalcium phosphate was added, andthe mixture was blended for 15 minutes. The remaining half of themagnesium stearate was added, and the mixture was blended for 5 minutes.The resulting granulation formed the CETP inhibitor composition.

A granulation of atorvastatin calcium was made using the followingprocess. The granulation contained 13.9 wt % atorvastatin trihydratehemicalcium salt, 42.4 wt % calcium carbonate (Pre-carb 150, availablefrom Mutchler Inc., Westwood, N.J.), 17.7 wt % microcrystallinecellulose (Avicel PH 101, FMC Corp.), 3.8 wt % croscarmellose sodium(AcDiSol, FMC Corp.), 0.5 wt % polysorbate 80 (Crillet 4HP, Croda,Parsippany, N.J.), 2.6 wt % hydroxypropyl cellulose (Klucel EF,Hercules, Wilmington, Del.), and 19.2 wt % pregelatanized starch (Starch1500, available from Colorcon, Inc., West Point, Pa.). To form thegranulation, the atorvastatin calcium, calcium carbonate,microcrystalline cellulose, and starch were charged into a fluidized bedgranulation apparatus. A granulating fluid comprising the polysorbate 80and hydroxypropyl cellulose dissolved in water was sprayed into thefluidized material to form the granules. The weight of water used wasequal to half the weight of the granulation. The granulation was thendried in the fluidized bed using air with an inlet temperature of about45° C. until an end point of less than 2% water loss on drying wasachieved. The granules were then milled using a Fitzpatrick M5A mill.The mill was fitted with a ˜0.03-inch rasping plate and a rasping baroperating at about 500 rpm in a knives forward direction(counter-clockwise). The average particle size of the granules was about105 μm using screen analysis. This composition comprised the HMG-CoAreductase inhibitor composition.

To form Example 1, 86 wt % of the CETP inhibitor composition and 14 wt %of the HMG-CoA reductase inhibitor composition were mixed together in atwin-shell blender, screened, mixed again, and then compressed intoslugs. The slugs were then milled using a mortar and pestle. The acidicconcentration-enhancing polymer HPMCAS comprised 38.7 wt % of Example 1,and atorvastatin calcium comprised 1.96 wt % of Example 1 for anHPMCAS/atorvastatin ratio of 19.7 (w/w).

Control 1 consisted of a mixture of crystalline atorvastatin calcium (2wt %) and the CETP inhibitor solid amorphous dispersion (98 wt %). Thecrystalline atorvastatin calcium and the solid amorphous dispersion weremixed together in a Turbula mixer, screened, mixed again, and thencompressed into slugs. The slugs were then milled using a mortar andpestle. The acidic concentration-enhancing polymer HPMCAS comprised 73.5wt % of Control 1, and atorvastatin calcium comprised 2 wt % of Control1, for an HPMCAS/atorvastatin ratio of 36.8 (w/w).

Control 2 consisted of a mixture of crystalline atorvastatin (1.42 wt%), the CETP inhibitor dispersion (62.50 wt %), and all of theexcipients used for both of the granulations (calcium carbonate—4.32 wt%, croscarmellose sodium—0.39 wt %, microcrystalline cellulose—3.07 wt%, pregelatinized starch—1.95, polysorbate 80—0.05 wt %, hydroxypropylcellulose—0.26, crospovidone—10.42, magnesium Stearate—0.26, dicalciumphosphate—15.36 wt %). The materials were mixed in a Turbula mixer,screened, mixed again and then compressed into slugs. The slugs werethen milled using a mortar and pestle. The acidicconcentration-enhancing polymer HPMCAS comprised 46.9 wt % of Control 2,and atorvastatin comprised 1.42 wt % of Control 1, for anHPMCAS/atorvastatin ratio of 33.0 (w/w).

Example 1, and Controls 1 and 2, were stored at 50° C. and 75% relativehumidity for 3 weeks to increase the rate of chemical and physicalchanges occurring in the materials in order to simulate a longer storageinterval in a typical storage environment.

Following storage, the samples were analyzed for atorvastatin purityusing HPLC. To analyze the samples by HPLC, a sample of the compositioncontaining about 0.4 mgA atorvastatin was added to a dissolving solvent.The dissolving solvent was made by combining 150 mL 50 mM ammoniumacetate (pH 7.0), 600 mL acetonitrile, and 250 mL methanol. Mobile phaseA was made by adding 3 mL acetic acid to 530 mL water, adjusting to pH4.0 with ammonium hydroxide, then adding 270 mL acetonitrile and 200 mLtetrahydrofuran. Mobile phase B was made by adding 1 mL acetic acid to100 mL water, adding half of the amount of ammonium hydroxide used toadjust Mobile phase A, then adding 700 mL acetonitrile and 200 mLtetrahydrofuran. The samples were analyzed using a Waters SpherisorbODS2 column, with a solvent flow rate of 1.5 mumin. Table 3 shows thesolvent gradient used.

TABLE 3 Time % A % B 0 100 0 15 100 0 35 0 100 50 0 100 51 100 0 60 1000The UV absorbance of atorvastatin and atorvastatin impurities weremeasured at a wavelength of 244 nm. The atorvastatin lactone impurityeluting after about 10.4 minutes was chosen as the basis for comparison.All impurity peak areas were added and the lactone impurity as percentof total peak area was calculated to give the degree of degradation.Results are shown in Table 4.

TABLE 4 Degree of Degradation Sample (wt %) Example 1 0.17 Control 11.55 Control 2 2.66

The results from Table 4 show that the atorvastatin in the sample ofControl 1 (atorvastatin mixed with the CETP inhibitor solid amorphousdispersion) contained 1.55 wt % lactone impurity. Control 2 (a mixturecontaining crystalline atorvastatin, CETP inhibitor solid amorphousdispersion, and the excipients used in both granulations) contained 2.66wt % lactone impurity. Example 1 showed that granulating theatorvastatin with excipients, then granulating the solid amorphousdispersion with excipients, followed by mixing the two granulations,provided improved atorvastatin stability. A relative degree ofimprovement in chemical stability was determined by taking the ratio ofthe degree of degradation of the drug in the control compositions andthe degree of degradation of the drug in Example 1. When compared withControl 1, Example 1 had a relative degree of improvement of 9.12 (1.55wt %/0.17 wt %). When compared with Control 2, Example 1 had a relativedegree of improvement of 15.6.

Examples 2 and 3

To form Example 2, equal weights of the granulated CETP inhibitorcomposition of Example 1 and the granulated HMG-CoA reductase inhibitorcomposition of Example 1 were blended as described in Example 1 and 200mg tablets were formed from the blend. The acidic polymer HPMCAScomprised 22.5 wt % of Example 2, and atorvastatin calcium comprised6.95 wt % of Example 2, for a ratio of HPMCAS to atorvastatin of 3.24.

To form Example 3, tablets containing separate layers of the CETPinhibitor composition of Example 1 and the HMG-CoA reductase inhibitorcomposition of Example 1 were manufactured. Each of the tablets ofExample 3 contained 400 mg of the dispersion granulation in one layerand 288 mg of the atorvastatin granulation in a second layer. The acidicconcentration-enhancing polymer HPMCAS comprised 26.2 wt % of Example 3,and atorvastatin comprised 5.82 wt % of Example 3 for a HPMCAS toatorvastatin ratio of 4.5.

Examples 2 and 3 were stored at 50° C. and 75% relative humidity for 3weeks, and analyzed using HPLC as described above. The results are shownin Table 5.

TABLE 5 Degree of Degradation Sample (wt %) Example 2 0.09 Example 30.04

Example 2 shows that tablets made by first forming separate granulations(one containing the solid amorphous dispersion and one containing theatorvastatin), and then blending the granulations to form a tablet,provide a dosage form with improved atorvastatin stability. ComparingExample 2 to Control 2 (a mixture containing crystalline atorvastatinCETP inhibitor dispersion, and the excipients used in bothgranulations), the relative degree of improvement was 29.6. Example 3showed that tablets made by forming separate layers of the solidamorphous dispersion granulation and the atorvastatin granulationprovided further improvement in atorvastatin stability. ComparingExample 3 to Control 2, the relative degree of improvement was 66.5.

Examples 4 to 11

Unitary dosage forms were made by the process described for Example 2with the exceptions noted in Table 6. The properties of the tablets aregiven in Table 7.

TABLE 6 HMG-CoA Acidic Polymer CETP Reductase Tablet to HMG CoAInhibitor Inhibitor Tablet Tablet CETP Atorvastatin ReductaseComposition Composition Weight Inhibitor Dose Calcium Dose InhibitorRatio Example (wt %) (wt %) (mg) (mg) (mg) (wt/wt) Example 4* 71.6528.10 278.45 30 10 8.3 Example 5* 24.11 75.64 827.57 30 80 1.0 Example6* 71.65 28.10 556.89 60 20 8.3 Example 7* 55.90 43.85 713.78 60 40 4.1Example 8* 82.22 11.53 678.44 90 10 23.1 Example 9* 48.75 51.00 1227.5790 80 3.1 Example 10* 90.84 8.91 878.45 120 10 33.0 Example 11* 83.4016.36 956.89 120 20 16.5 *0.25 wt % Magnesium stearate was blended withthe two compositions prior to forming the tablets.

TABLE 7 Modified Oval Tablet Cross Tablet Tablet Tablet Size SectionArea Hardness Strength Example (cm × cm) (cm²) (kP) (kP/cm²) Example 40.6126 × 1.2253 0.6 13.2 22.0 Example 5 0.8806 × 1.7615 1.2 31.9 26.6Example 6 0.7719 × 1.6492 1.0 14.2 14.2 Example 7 0.8385 × 1.6772 1.18.2 7.5 Example 8 0.8245 × 1.6492 1.1 23.4 21.3 Example 9 1.0617 ×1.8999 1.6 45.7 28.6 Example 10 0.8987 × 1.7976 1.3 8.6 6.6 Example 110.9246 × 1.8491 1.3 9.4 7.2

Samples of the tablets of Examples 6, 7, 10, and 11 were stored for 6weeks at 40° C. and 75% RH. Table 8 gives the concentration of thelactone degradant in the tablet before and after storage, as well as thedegree of degradation of the atorvastatin calcium. These data show thatformation of the tablets using the granulated compositions results inlow degrees of degradation for atorvastatin calcium.

TABLE 8 Degradant Concentration (wt %) Degree of After Storage 6 weeksDegradation Example Before Storage at 40° C./75% RH (wt %) Example 60.05 0.08 0.03 Example 7 0.06 0.07 0.01 Example 10 0.09 0.12 0.03Example 11 0.03 0.10 0.07

Example 12

A granulation of the HMG-CoA reductase inhibitor atorvastatin and asolid amorphous dispersion containing a CETP inhibitor and aconcentration-enhancing polymer were combined and stored at 40° C. and75% relative humidity for 6 weeks. The composition showed acceptableamounts of chemical degradation of the HMG-CoA reductase inhibitor.

A spray-dried solid amorphous dispersion containing 40 wt % torcetrapiband 60 wt % hydroxypropyl methyl cellulose acetate succinate (highgranular grade available from Shin Etsu, located in Japan) (referred toherein as “HPMCAS-HG”) was formed using a process similar to the onedescribed in Example 1 with the follow exceptions. The spray solutioncontained 20 g torcetrapib, 30 g HPMCAS-HG, and 450 g acetone. The spraysolution was pumped into to the PSD-1 spray drier equipped with apressure atomizer (Spraying Systems Pressure Nozzle and Body (SK80-16)). The PSD-1 was equipped with a 9-inch chamber extension. Thespray drier was also equipped with a diffuser plate having a 1% openarea. The spray solution was pumped to the spray drier at about 145gm/min, with an atomization pressure of about 250 psi. Drying gas(nitrogen) was circulated through the diffuser plate at an inlettemperature of about 97° C. The evaporated solvent and wet drying gasexited the spray drier at a temperature of 46° C. The solid amorphousdispersion was post-dried using a Gruenberg single-pass convection traydryer operating at 40° C. for about 16 hours.

The spray-dried solid amorphous dispersion was evaluated in an in vitrodissolution test using a microcentrifuge method. In this test, 4.5 mg ofthe spray -dried solid amorphous dispersion was placed into amicrocentrifuge tube. The tube was placed in a 37° C. sonicating bath,and 1.8 mL phosphate buffered saline (PBS) at ph 6.5 and 290 mOsm/kg wasadded, resulting in a torcetrapib concentration of 1000 μg/mL if all ofthe drug dissolved. The sample was quickly mixed using a vortex mixerfor about 60 seconds. The sample was centrifuged at 13,000 G at 37° C.for 1 minute. The resilting superatant solution was then sampled anddiluted 1:6 (by volume) with methanol and then analyzed byhigh-performance liquid chromatography (HPLC). The contents of the tubewas mixed on the vortex mixer and allowed to stand undisturbed at 37° C.until the next sample was taken. Samples were collected at 4, 10, 20,40, 90, and 1200 minutes. The concentrations of drug obtained in thesesamples are shown in Table 9, which represent the average of duplicatetests. The results using crystalline drug are included in Table 9 for

TABLE 9 Torcetrapib Time Concentration AUC Sample (min) (μg/mL)(min-μg/mL) Solid 0 0 0 Amorphous 4 79 200 Dispersion 10 22 500 20 18700 40 17 1,000 90 18 1,900 1200 210 129,000 Crystalline Drug 0 0 0 4 <1<2 10 <1 <8 20 <1 <18 40 <1 <38 90 <1 <88 1200 <1 <1,200

The results of these dissolution tests are summarized in Table 10, whichshows the maximum concentration of torcetrapib in solution during thefirst 90 minutes of the test (MDC₉₀), the area under the aqueousconcentration versus time curve after 90 minutes (AUC₉₀), and theconcentration at 1200 minutes (Cl₂₀₀).

TABLE 10 Torcetrapib Conc. Aqueous- in the AUC₉₀ Soluble DispersionReceptor MDC₉₀ (min- Sample Polymer (wt %) Solution (μg/mL) μg/mL) C₁₂₀₀(μg/mL) Solid HPMCAS-HG 40 PBS 79 1,900 210 Amorphous DispersionCrystalline None NA PBS <1 <88 <1 Drug

The results summarized in Table 10 show that the solid amorphousdispersion provided concentration enhancement relative to crystallinedrug. The solid amorphous dispersion provided a C_(max,90) value thatwas greater than 79-fold that of the crystalline drug, and an AUC₉₀value that was greater than 21-fold that of the crystalline drug.

To form Example 12, 78 wt % of the CETP inhibitor solid amorphousdispersion and 22 wt % of the HMG-CoA reductase inhibitor composition ofExample 1 were mixed together in a twin-shell blender, screened, mixedagain, and then compressed into slugs. The acidicconcentration-enhancing polymer HPMCAS-HG comprised 47 wt % of Example12, and atorvastatin calcium comprised 0.93 wt % of Example 12 for anHPMCAS-HG/atorvastatin ratio of 15 (w/w).

Example 12 was stored at 40° C. and 75% relative humidity for 6 weeks toincrease the rate of chemical and physical changes occurring in thematerials in order to simulate a longer storage interval in a typicalstorage environment. Following storage, the sample was analyzed foratorvastatin purity using HPLC as described in Example 1. The resultsare summarized in Table 11 and show that the sample had a degree ofdegradation of 0.16 wt %, demonstrating that blending an HMG-CoAreductase inhibitor granulation with a solid amorphous dispersionresults in acceptably low degrees of degradation of the HMG-CoAreductase inhibitor.

TABLE 11 Degradant Concentration (wt %) After Storage 6 weeks at Degreeof Degradation Example Before Storage 40° C./75% RH (wt %) Example 120.05 0.21 0.16

The terms and expressions which have been employed in the foregoingspecification are used therein as terms of description and not oflimitation, and there is no intention, in the use of such terms andexpressions, of excluding equivalents of the features shown anddescribed or portions thereof, it being recognized that the scope of theinvention is defined and limited only by the claims which follow.

1. A unitary dosage form comprising: (a) a cholesteryl ester transferprotein inhibitor composition comprising a solid amorphous dispersion ofa cholesteryl ester transfer protein inhibitor and an acidicconcentration-enhancing polymer selected from the group consisting ofhydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetatetrimellitate and carboxymethyl ethyl cellulose; and (b) an HMG-CoAreductase inhibitor composition comprising an HMG-CoA reductaseinhibitor; wherein said solid amorphous dispersion and said HMG-CoAreductase inhibitor are substantially separate from one another in saiddosage form.
 2. The unitary dosage form of claim 1 wherein said dosageform comprises a plurality of granules of said cholesteryl estertransfer protein inhibitor composition and a plurality of granules ofsaid HMG-CoA reductase inhibitor composition.
 3. The unitary dosage formof claim 1 wherein said dosage form comprises at least two layers, atleast one of said layers comprising said cholesteryl ester transferprotein inhibitor composition and another of said layers comprising saidHMG-CoA reductase inhibitor composition.
 4. The unitary dosage form ofclaim 1 wherein at least one of said cholesteryl ester transfer proteininhibitor composition and said HMG-CoA reductase inhibitor compositionhas a non-acidic coating.
 5. The unitary dosage form of claim 1 whereinsaid dosage form is selected from the group consisting of a tablet,caplet, pill, capsule, powder, and a kit comprising one or more tablets,caplets, pills, capsules, sachets, powders, or solutions to be takentogether.
 6. The unitary dosage form of claim 1 wherein said dosage formprovides at least one of: (a) an improvement in the maximumconcentration of said cholesteryl ester transfer protein inhibitor in ause environment of at least 1.25-fold relative to a control compositionconsisting essentially of said cholesteryl ester transfer proteininhibitor alone; (b) an area under the concentration of said cholesterylester transfer protein inhibitor versus time curve in the useenvironment for any period of at least 90 minutes between the time ofintroduction into the use environment and about 270 minutes followingintroduction to the use environment that is at least 2-fold that of saidcontrol composition consisting essentially of said cholesteryl estertransfer protein inhibitor alone; (c) a maximum concentration of saidcholesteryl ester transfer protein inhibitor in the blood of at least1.25-fold relative to a control composition consisting essentially ofsaid cholesteryl ester transfer protein inhibitor alone; and (d) animprovement in the relative bioavailability of said cholesteryl estertransfer protein inhibitor in the use environment of at least 1.25-foldrelative to said control composition consisting essentially of saidcholesteryl ester transfer protein inhibitor alone.
 7. The unitarydosage form of claim 1 wherein said composition provides an improvementin chemical stability of said HMG-CoA reductase inhibitor relative to acontrol composition consisting essentially of a blended mixture of theindividual components of said cholesteryl ester transfer proteininhibitor composition and the individual components of said HMG-CoAreductase inhibitor composition.
 8. The unitary dosage form of claim 1wherein said HMG-CoA reductase inhibitor is selected from the groupconsisting of fluvastatin, lovastatin, pravastatin, atorvastatin,simvastatin, cerivastatin, rivastatin, mevastatin, velostatin,compactin, dalvastatin, fluindostatin, rosuvastatin, pitivastatin,dihydrocompactin, and pharmaceutically acceptable forms thereof.
 9. Theunitary dosage form of claim 1 wherein at least one of said cholesterylester transfer protein inhibitor composition and said HMG-CoA reductaseinhibitor composition further comprises a base.
 10. The unitary dosageform of any of claims 1-8 wherein said HMG-CoA reductase inhibitor isatorvastatin or pharmaceutically acceptable forms thereof.
 11. A methodfor forming a unitary dosage form comprising: (a) forming a solidamorphous dispersion comprising a cholesteryl ester transfer proteininhibitor and a concentration-enhancing polymer selected from the groupconsisting of hydroxypropyl methyl cellulose acetate succinate,hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate,cellulose acetate trimellitate and carboxymethyl ethyl cellulose; and(b) combining said solid amorphous dispersion with an HMG-CoA reductaseinhibitor to form said unitary dosage form; wherein said solid amorphousdispersion and said HMG-CoA reductase inhibitor are combined so thatsaid solid amorphous dispersion and said HMG-CoA reductase inhibitor aresubstantially separate from one another in said dosage form.
 12. Themethod of claim 11 wherein said step (b) further comprises the step offorming a plurality of granules comprising said solid amorphousdispersion, and further comprising the step of forming an HMG-CoAreductase inhibitor composition, and then mixing said HMG-CoA reductaseinhibitor composition with said plurality of granules.
 13. The method ofclaim 11 wherein said step (b) further comprises forming at least twolayers, at least one of said layers comprising said solid amorphousdispersion and another of said layers comprising said HMG-CoA reductaseinhibitor.